Satomi Kasashima

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.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

Biliary Papillary Tumors Share Pathological Features With Intraductal Papillary Mucinous Neoplasm of the Pancreas

Recently, attention has been drawn to papillary neoplasm of the pancreatobiliary systems. In the pancreas, the disease entity of intraductal papillary mucinous neoplasm (IPMN‐P) is widely recognized. In contrast, the pathological characteristics of biliary papillary tumors, such as biliary papilloma(tosis) and papillary cholangiocarcinoma, have not yet been well documented. In this study, we compared the pathological features and post‐operative prognosis among biliary papillary tumors (10 cases of biliary papilloma(tosis) and 22 cases of papillary cholangiocarcinoma), conventional non‐papillary cholangiocarcinoma (15 cases), and IPMN‐P (31 cases). Macroscopically, all biliary papillary tumors were characterized by the prominent intraductal papillary proliferation, and macroscopic mucin‐hypersecretion was seen in 9 of 32 cases (28%). Histologically, biliary papillary tumors consisted of three types of tumor cells (pancreaticobiliary, intestinal and gastric types), whereas only the pancreaticobiliary type was observed in non‐papillary cholangiocarcinoma. Immunohistochemically, biliary papillary tumors were characterized by the common expression of MUC2, CDX2 and cytokeratin 20. In addition, biliary papillary tumors could be associated with two types of invasive lesions: tubular adenocarcinoma (9 cases) and mucinous carcinoma (5 cases). Patients with tubular adenocarcinoma had a poor prognosis compared to non‐invasive papillary tumor or papillary tumor with mucinous carcinoma. These pathological characteristics and the survival status of biliary papillary tumors were different from those of non‐papillary cholangiocarcinoma, and rather closely resembled those of IPMN‐P. In conclusion, biliary papillary tumors may be the biliary counterpart (intraductal papillary neoplasm of the bile duct) of IPMN‐P. (HEPATOLOGY 2006;44:1333–1343.)

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.

A new clinicopathological entity of IgG4-related inflammatory abdominal aortic aneurysm

OBJECTIVE Recently, the relationship between immunoglobulin (Ig)G4 and idiopathic sclerosing lesions has attracted much attention. IgG4-related disease was first described with regard to the pancreas (autoimmune pancreatitis), and has been expanded to various organ systems. We previously reported that inflammatory abdominal aortic aneurysm (IAAA) could be one of the manifestations of IgG4-related disease. In this study, we tried to elucidate the clinical characteristics of IgG4-related IAAA. METHODS This study consisted of 23 cases of IAAA and 40 cases of atherosclerotic abdominal aortic aneurysm (AAA). Clinical presentation, laboratory findings, and pathological features were examined. Aneurysms of 13 cases histologically corresponded to IgG4-related IAAA. RESULTS Those cases accounted for 5% of all surgical AAAs, and 57% of IAAAs. Compared to non-IgG4-related IAAA, IgG4-related cases were characterized by less frequent association with abdominal or back pain. Serum IgG4 concentrations were significantly elevated in IgG4-related cases. Interestingly, patients with IgG4-related IAAA frequently showed an allergic constitution, such as drug allergy, autoimmune diseases, high serum IgE concentrations, and a high titer of antinuclear antibody. Pathologically, IgG4-related cases were characterized by more significant thickening of the adventitia and more numerous IgG4-positive plasma cell infiltrations. Three non-IgG4-related cases showed aneurysmal rupture at the time of first presentation, whereas no IgG4-related cases showed rupture. CONCLUSION Recognizing a new disease entity of IgG4-related IAAA seems important because this was clinically and pathologically different from conventional aAAA and non-IgG4-related IAAA.

A case of multiple immunoglobulin G4–related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm

Immunoglobulin G4 (IgG4)-related disease can occur in various organs, most of which are glandular or ductal tissues. Here, we report a case of multiple IgG4-related vascular lesions. A 63-year-old patient was found to have an abdominal aortic aneurysm and a tumorous lesion around the right coronary artery. The surgically resected aneurysmal wall and a tumorous lesion of the right coronary artery showed similar histologic features including diffuse lymphoplasmacytic infiltration, occasional eosinophils, and obliterative phlebitis. Immunohistochemically, numerous IgG4-positive plasma cells were evident within the lesions. The serum concentrations of IgG4 in the preoperative period was 456 mg/dL (reference range, <135), which decreased to 242 mg/dL 2 weeks after surgery. We made a diagnosis of multiple IgG4-related periarteritis manifesting as an abdominal aortic aneurysm and a tumorous nodule of the coronary artery. This case report suggested that IgG4-related disease can occur in the vascular system and manifest as an aneurysm or a periarterial mass lesion.

A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta

OBJECTIVE Immunoglobulin G4-related sclerosing disease (IgG4-SD) has recently been reported to occur in the cardiovascular system and manifest as inflammatory abdominal aortic aneurysm. Thoracic aortic lesions are often associated with aortitis in several divergent etiologies. Thus, this study was performed to review thoracic aortic lesions from the aspect of IgG4-SD and to elucidate the clinicopathologic characteristics of this subgroup in the thoracic aorta. METHODS The study comprised 125 patients, including 71 with thoracic aortic aneurysm (TAA), 44 with aortic dissection, 7 with Takayasu aortitis, and 3 with infectious aortitis. IgG4-SD was identified by diffuse infiltration of numerous IgG4-positive plasmacytes by immunohistochemical examinations. Clinicopathologic features were compared between IgG4-related and IgG4-unrelated lesions. RESULTS Among the 125 patients, IgG4-SD was found in 5 patients with TAA but was not detected in the other subgroups of thoracic aortic lesion. IgG4-related TAA included one case of lymphoplasmacytic aortitis, 1 case of inflammatory aneurysm, and three cases of atherosclerotic aneurysms. Patients with IgG4-related TAA showed clinicopathologic features similar to patients with IgG4-SD: male gender, old age, history of bronchial asthma and allergies, elevation of white blood cell counts, C-reactive protein levels, and IgG4 and IgE concentrations (in one patient); eosinophilic infiltration, obliterative phlebitis, lymph follicle formation, and perineural inflammation. In addition, compared with IgG4-unrelated TAA, IgG4-related TAA was characterized by clinically more frequency of involvement of the aortic arch (P = .002), saccular formation (P = .003), and fibrous adhesion to surrounding tissue (P < .001), and histopathologically thicker entire aortic wall and adventitia (P < .001 each). CONCLUSIONS IgG4-SD is involved in 4% of all thoracic aortic lesions and uniformly presents in the form of an aneurysm with distinct histologic and clinicopathologic features. IgG4-SD represents one, albeit rare, etiology of TAA, especially those originating in the aortic arch.

IgG4-related inflammatory abdominal aortic aneurysm.

Purpose of reviewIgG4-related systemic disease is a recently proposed entity characterized by high serum IgG4 concentrations, sclerosing inflammation containing numerous IgG4-positive plasmacytes, dramatic responsiveness to steroid therapy, and occurrence of multiple organs. This review described that some cases of inflammatory abdominal aortic aneurysm (IAAA) have similar clinicopathological features that are now considered to represent aortic lesions of IgG4-related systemic disease under the concept of IgG4-related IAAA. Recent findingsIgG4-related IAAA is characterized by high serum IgG4 and immunoglobulin E levels, high titers of antinuclear antibodies, and high prevalence of allergic disorders such as bronchial asthma. The patients show a risk of developing IgG4-related systemic diseases in other organs during their life. Histologically, sclerosing inflammation containing numerous IgG4-positive plasmacytes is observed predominantly in the adventitia. Similar lesions have also been reported in the thoracic aorta and large arteries. SummaryRecognition of the fact that IgG4-related systemic disease could involve the vascular lesions offers potential new management of those. However, only 3 years have passed since the first report of IgG4-related IAAA. Further studies are necessary to elucidate other vascular lesions associated with IgG4-related systemic disease, the usefulness of steroid therapy for the management of IgG4-IAAA, and underlying pathological and immunological characteristics.

Retroperitoneal and aortic manifestations of immunoglobulin G4-related disease

Retroperitoneal fibrosis is one of the prototypic manifestations of immunoglobulin G4 (IgG4)-related disease (IgG4-RD), but there is growing evidence that the aorta is also involved. These 2 conditions are closely linked, and based on the epicenter of the disease, the clinical manifestations can be classified as retroperitoneal fibrosis, inflammatory abdominal aortic aneurysm (including a combination of the 2), and thoracic aortitis. IgG4-RD is responsible for only a subset (∼50%) of cases of retroperitoneal fibrosis and inflammatory aortic aneurysms. Histological features include an extensive lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, fibrosis arranged in a storiform pattern, moderate tissue eosinophilia, and partially or completely obliterated veins. Among the 3 layers comprising the aorta, the adventitia is most susceptible to IgG4-related inflammation. The inflammatory process can also disrupt the lamellar elastic fibers in the media, which is seemingly a critical event leading to aneurysmal transformation. Steroid therapy is effective for both retroperitoneal and aortic lesions, as it is for the other manifestations of IgG4-RD. The risk of rupture appears to be low in patients with IgG4-related aortic aneurysms, but immunosuppressive therapy may trigger this critical complication by reducing the wall thickness.

Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive supranuclear palsy and corticobasal degeneration

Abstract. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are clinically characterized by atypical parkinsonism and cognitive disorders and classified in the same histopathological category showing neuronal and glial neurofibrillary tangles (NFTs). To characterize the vulnerability of the forebrain and midbrain cholinergic systems in PSP and CBD, we performed a comparative study of cholinergic neuronal changes in the nucleus basalis of Meynert (NBM) and the laterodorsal tegmental and pedunculopontine tegmental nuclei (LdtgN and PptgN) of brains obtained at autopsy (three cases of PSP, one case of CBD and six cases without neurological diseases) by immunohistochemistry for choline acetyltransferase (ChAT) and Gallyas-Braak staining. In the NBM, the number of neurons and the ChAT-positivity rate of remaining neurons were decreased more in CBD than PSP. On the other hand, in the PptgN and LdtgN neurons were reduced much more, and more NFTs were observed in PSP than CBD. PSP showed a severe decrease of neurons and the ChAT-immunopositive neurons in the LdtgN but less in the PptgN. In CBD, there was a mild deletion of the ChAT-immunostained neurons in the PptgN, but not in the LdtgN. In PSP, cholinergic neurons in the LdtgN are likely to be more vulnerable than PptgN and NBM.