Atsuhiro Kawashima

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.

Expression of αv Integrin Family in Gastric Carcinomas: Increased αvβ6 is Associated with Lymph Node Metastasis

Summary To investigate the alterations as to integrin expression in human gastric carcinomas, we analyzed the av subunit and 5 types of β subunits using reverse transcription-polymerase chain reaction (RT-PCR) and competitive RT-PCR. The incidence of αv, β6 and β8 expression was significantly higher in carcinoma tissues than in non-neoplastic gastric mucosal tissues (NGMTs). Out of 18 carcinoma cases with coexpression of αv and β6 subunits, which was demonstrated by RT-PCR, 17 cases (94%) showed lymph node metastasis (p = 0.0033). This tendency was confirmed by immunohistochemistry; most cases (23/28, 82%) in which αvβ6 integrin was immunohistochemically detected showed lymph node metastasis (p = 0.0193). RT-PCR and immunohistochemical studies showed that gastric carcinoma tissues expressed β5 subunit in all cases. Furthermore, in a quantitative analysis using competitive RT-PCR, the mean level of β5 expression was approximately 140 times higher in gastric carcinomas than in NGMTs. Most gastric carcinoma cases (27/38, 71%) were immunohistochemically positive for β8 subunit. These findings suggest that some members of the αv integrin family (αvβ5, αvβ6, αvβ8) are up-regulated, and that αvβ6 integrin may be involved in the lymphatic metastasis of gastric carcinomas.

IMMUNOHISTOCHEMICAL ANALYSIS OF SEVERAL PROTEOLYTIC ENZYMES AS PARAMETERS OF CARTILAGE DEGRADATION

Osteoarthritis is the most common joint disease in humans. It is characterized by a gradual loss of extracellular matrix components of articular cartilage such as collagen and proteoglycan. Presently, however, emphasis is placed on enzymes exerting a strong influence on cartilage degradation. These enzymes include matrix metalloproteinases (MMP), their specific inhibitors (TIMP) and the plasminogen activator/inhibitor system. We applied monoclonal antibodies against MMP-1, -2, -3, -9 and their inhibitors TIMP-1/-2, as well as against urokinase-plasminogen activator u-PA and its inhibitor PAI to investigate their influence on articular cartilage degradation in patients with varusgonarthritis. We examined the cartilage of the lateral and medial compartments of 20 tibia plateaus, which can present with slight and severe cartilage degradations at the same time. In doing so, we tried to show whether or not immunohistological detection of enzymes could serve as a parameter for chondral degradation. The strongest immunoreaction for all enzymes was noted in the superficial layer of articular cartilage both medially and laterally. Between medial and lateral compartments, however, there were striking differences in the immunoreaction intensity of chondrocytes for MMP-1 and -3 as well as for TIMP-1 and u-PA. We noted that in cartilage with more advanced degradation, the immunoreaction for these enzymes was significantly higher in medial than in lateral compartments (p < 0.05). At the immunohistological level, a direct correlation between the grade of cartilage degradation and immunoreaction intensity was found. Our results corroborate the assumption that the expression of certain matrix-degradating enzymes serves as a parameter for the grade of cartilage degradation.

Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor α correlates with metastatic ability in a human osteosarcoma cell line

We have examined the correlation between matrix metalloproteinase (MMP) expression and metastatic properties of a low metastatic osteosarcoma cell line, osteosarcoma takase (OST), under stimulation by tumour necrosis factor α (TNFα). In vivo, OST cells exhibited significantly increased colonization in the lungs of nude mice in a dose-dependent manner when they were treated by TNFα prior to injection. In vitro, TNFα enhanced tumour cell invasion through the reconstituted basement membrane in a transwell chamber up to 2.5-fold. Gelatin zymography and sandwich enzyme immunoassays demonstrated marked production of MMP-9 [92-kDa gelatinase/type IV collagenase (gelatinase B)] but not MMP-2 [72-kDa gelatinase/type IV collagenase (gelatinase A)], MMP-3 (stromelysin-1) or MMP-7 (matrilysin). Motility of the tumour cells and adhesion to cultured endothelial cells were slightly increased by the TNFα treatment up to 1.6-fold and 1.4-fold, respectively, while the growth rate was decreased. These results suggest that upregulation of MMP-9 together with enhanced motility and endothelial adhesion contribute to the increased metastatic ability of OST cells induced by TNFα treatment.

Evaluation of a new histologic staging and grading system for primary biliary cirrhosis in comparison with classical systems

Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions.

Borderline chondrosarcoma of long and flat bones

We reviewed histological and clinical findings of six cases of borderline chondrosarcoma and examined the expression of collagen types I, II, III, V, and VI by immunohistochemical analysis of these tumors. Borderline chondrosarcoma is defined as a cartilaginous tumor of bone resembling enchondroma on the basis of histomorphology. Clinically the tumor causes intermittent vague pain unrelated to physical activities. On radiographs borderline chondrosarcoma is characterized by evidence of endosteal erosion. We observed local recurrences in two cases treated by intralesional excision and marginal excision, and one of those cases died of inoperable local tumor recurrence. In our histological analysis based on tissue patterns, there were enchondromatous patterns in five cases, and chondrosarcomatous patterns in four cases. In the second recurrent tumor in one case, a chondrosarcomatous pattern was newly observed, and the recurrent tumor was found to be a low-grade chondrosarcoma cytologically in the other case. In the tumor matrix immunoreactivity for collagen types II and VI was predominant, with collagen types I, III, and V showing heterogeneous expression in some cases. In all cases rimming of tumor lobules with collagen types I and V was absent. Immunoreactivity for collagen type II in the cytoplasm of tumor cells was found in four cases and all three recurrent tumors. Borderline chondrosarcoma, as defined by histology, clinical symptoms and radiological appearance, shows a collagen distribution pattern similar to that of low-grade chondrosarcoma. These findings are in accordance with the clinical outcome of borderline chondrosarcoma which parallels that of low-grade chondrosarcoma. Thus borderline chondrosarcoma may be best treated by wide en-bloc excision rather than curettage.