Hiroshi Kurumaya

Igg4-related Sclerosing Cholangitis With and Without Hepatic Inflammatory Pseudotumor, and Sclerosing Pancreatitis-associated Sclerosing Cholangitis: Do They Belong to a Spectrum of Sclerosing Pancreatitis?

Sclerosing cholangitis (SC) is a heterogeneous disease entity. Different etiologies such as choledocholithiasis, biliary tumor, or pericholangitis can manifest as SC. Hepatic inflammatory pseudotumor (IP) is rarely associated with SC (sclerosing cholangitis associated with hepatic inflammatory pseudotumor; SC-hepatic IP), but sclerosing pancreatitis (SP) is not infrequently associated with bile duct lesions (sclerosing pancreatitis-associated sclerosing cholangitis; SP-SC). In this study, we compared the histologic changes of hepatic hilar and extrahepatic bile duct lesions of SC (7 cases), SC-hepatic IP (5 cases), SP-SC (5 cases), and typical primary sclerosing cholangitis (PSC) (5 cases). Histologically, all SP-SC cases showed extensive and dense fibrosis with marked lymphoplasmacytic infiltration, many eosinophils, and obliterative phlebitis. Four cases of SC showed bile duct lesions similar to those of SP-SC, whereas other three cases of SC showed milder lymphoplasmacytic infiltration, scant eosinophilic cell infiltration, and no obliterative phlebitis. All SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC. Immunohistochemically, many IgG4-positive plasma cells were found in the bile duct lesions of all SP-SC cases, 4 SC cases with marked lymphoplasmacytic infiltration, and all SC-hepatic IP cases. By contrast, IgG4-positive plasma cells were scarce or hardly found in the remaining 3 SC cases and all PSC cases. In conclusion, 4 SC cases and all SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC, suggesting that these three conditions may be a single disease entity. Their pathogenesis may be similar or closely related to that of SP, and in that respect they may represent an IgG4-related biliary disease. They may respond to steroid therapy as SP does.

Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner'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 Sjögrens 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 γ-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.

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.)

PRIMARY PULMONARY ARTERY SARCOMA. Report of Two Autopsy Cases Studied by Immunohistochemistry and Electron Microscopy, and Review of 110 Cases Reported in the Literature

Two cases of primary pulmonary artery sarcoma are reported. The patient in the first case was a 61‐year‐old male with a two‐year history of cough and exertional dyspnea, who died of intractable cardiac failure two months after admission without establishment of a diagnosis related to the etiology of cardiac failure. Autopsy revealed a sessile tumor within the pulmonary trunk and a solitary metastatic lesion in the lung. Histologic, immunohistocyto‐chemical and electron microscopic studies were performed and a diagnosis of malignant mesenchymoma was made. The patient in the second case was a 32‐year‐old male complaining of exertional dyspnea and back pain. Radiologic studies indicated a mediastinal tumor involving the pulmonary artery. Exploratory thoracotomy revealed that the mediastinal mass arose from the left pulmonary artery. He died of respiratory failure 26 months after onset of his initial symptoms. Histologic, immunocytochemical and electron microscopic studies of both surgical and autopsy materials revealed a malignant fibrous histiocytoma. One hundred ten previously reported cases of this tumor are reviewed, and its clinicopathologic and morphologic features and probable histogenesis are discussed. ACTA PATHOL JPN 38: 883∼896, 1988.

Multiple cysts in the hepatic hilum and their pathogenesis

Multiple serous cysts involving only the hepatic hilum and larger portal tracts were found incidentally in 8 autopsy cases with several underlying liver diseases. The cysts were mostly small in size, and did not communicate with the lumena of the biliary tree. The lining of the cysts consisted of a single layer of columnar or cuboidal epithelium and the surrounding fibrous tissue was scanty. These were not associated with polycystic disease of the kidneys or cystic dilatation of the biliary tree. Cysts were absent in the liver parenchyma and an association with von Meyenburg complexes was rare. In the vicinity of the cysts there were many lobules of the glands which are physiologically present in the periductal connective tissue of the large intrahepatic bile ducts. It was noted that some of these glandular elements around the cysts disclosed varying degrees of cystic luminal dilatations. Almost all patients with such cysts had severe portal hypertension and over a half had occluding thromboemboli in the portal veins. These results lead us to propose the hypothesis that multiple cysts involving the hepatic hilum and the larger portal tracts are derived from the periductal glands in close association with an intrahepatic circulatory disturbance of the portal venous system.

Epithelial-mesenchymal transition induced by biliary innate immunity contributes to the sclerosing cholangiopathy of biliary atresia

Infections of Reoviridae consisting of a double‐stranded RNA (dsRNA) genome and the biliary innate immune response to dsRNA are implicated in the aetiopathogenesis of biliary atresia (BA). Epithelial–mesenchymal transition (EMT) has recently been proposed as a mechanism behind the sclerosing cholangitis in BA. We hypothesized that the innate immune response to dsRNA in biliary epithelial cells plays an important role in peribiliary fibrosis via biliary EMT. Experiments using cultured human biliary epithelial cells revealed that stimulation with poly(I : C) (a synthetic analogue of viral dsRNA) increased the expression of basic fibroblast growth factor (bFGF, an EMT‐inducer), S100A4 (a mesenchymal marker) and Snail (a transcriptional factor), and decreased that of epithelial markers (biliary‐type cytokeratin 19 and E‐cadherin) and Bambi (TGF‐β1 pseudoreceptor). The expression of TGF‐β1 (EMT‐inducer) and vimentin (a mesenchymal marker) was not affected by poly(I : C). Both EMT‐inducers, bFGF and TGF‐β1, evoked a decrease and increase in the expression of the epithelial markers and of vimentin respectively, and the expression of Bambi was down‐regulated on stimulation with bFGF. Combined treatment with bFGF and TGF‐β1 quickly and completely induced a transformation of morphology as well as change from epithelial to mesenchymal features in cultured biliary epithelial cells. Immunohistochemistry revealed that biliary epithelial cells lining extrahepatic bile ducts and peribiliary glands in BA frequently show a lack of epithelial markers and an aberrant expression of vimentin. Moreover, the biliary epithelium showing sclerosing cholangitis expressed bFGF accompanied by bFGF‐positive mononuclear cells. In conclusion, the EMT may contribute to the histogenesis of sclerosing cholangiopathy, and the biliary innate immune response to dsRNA viruses induces biliary epithelial cells to undergo EMT via the production of bFGF and the increased susceptibility to TGF‐β1 caused by the down‐regulation of Bambi expression. Copyright

Overlap of idiopathic portal hypertension and scleroderma: report of two autopsy cases and a review of literature.

Abstract Idiopathic portal hypertension (IPH) is characterized by dense fibrosis of portal tracts and portal venous obliteration. Little is known about the etiopathogenesis of IPH. Association of various autoimmune diseases such as systemic lupus erythematosus in IPH suggests that IPH may share immunological disturbances with such autoimmune diseases. We recently experienced two autopsy cases presenting with both diffuse scleroderma and IPH. Dense fibrosis was found in both the dermis and intrahepatic portal tract of these cases. In addition, small vascular damages were commonly observed to various degrees in these fibrotic areas of both organs. The activation of fibroblasts and vascular damages mediated by various growth factors and cytokines reportedly involved in the dermis in scleroderma might have also been operative in portal tracts in these two cases of IPH. A review of literature disclosed eight overlapping cases of IPH and scleroderma (middle‐ to old‐aged females), and scleroderma was diagnosed earlier than IPH. These findings suggest that similar pathogenetic processes are operative in the dermis as well as in the portal tracts of the liver in these cases.

Thymic carcinoma involving the thyroid gland: Report of two cases

Two new cases of thymic carcinoma involving the thyroid gland and manifesting as thyroid tumors are presented. One tumor occurred within the thyroid gland and the other totally involved the thyroid gland. Microscopically they showed lobular architecture separated by fibrous bands and consisted of solid islands of squamoid to spindled epithelial cells with whorl formation resembling Hassalls corpuscle and variable amounts of lymphocytes. The squamoid to spindled epithelial cells were positive for cytokeratin but negative for thyroglobulin and calcitonin and the majority of lymphocytes showed a T-cell phenotype. One of the two cases had been diagnosed initially as squamous cell carcinoma of the thyroid. This type of thyroid carcinoma is relatively rare, but it should be differentiated from other types of thyroid carcinomas, especially squamous cell carcinoma, medullary carcinoma, or anaplastic carcinoma of the thyroid.

Diffuse Sclerosing Variant of Papillary Carcinoma of the Thyroid Report of Three Cases

Three cases of an unusual diffuse sclerosing variant of papillary carcinoma were found among 370 consecutive malignant tumors of the thyroid gland retained in the surgical pathology files of Kanazawa University Hospital over the last 10 years. The tumors were characterized by diffuse involvement of one or both lobes of the thyroid, dense fibrosis, papillary carcinoma with marked squamous metaplasia and abundant psammoma bodies, heavy lymphocytic infiltration and extensive lymphatic permeation. In two cases, the neoplasms showed more aggressive regional lymph node metastases and local invasion; the patient in the first case underwent surgery three times after initial radical surgery because of regional lymph node recurrences, and the second case showed direct invasion of the thyroid tumor to the larynx and distant metastasis to the lungs. Although the number of examined cases was small, the findings suggest that the diffuse sclerosing variant type has a less favorable prognosis and should be differentiated from papillary carcinomas with excellent prognosis.

Solitary fibrous tumor in the pelvic cavity with hypoglycemia: report of a case.

A case of solitary fibrous tumor (SFT) in the pelvic cavity with hypoglycemia is reported. The patient was a 60-year-old man who was referred to our hospital for a closer examination of hypoglycemia. Computed tomography demonstrated a mass, measuring 14 × 9 cm in size, in the pelvic cavity. Magnetic resonance imaging showed the mass to have a low signal intensity on T1-weighted images and a high intensity on T2-weighted images. Laparotomy revealed no peritoneal dissemination nor lymph node metastasis. An en bloc excision of the tumor was performed with a good recovery, and the hypoglycemia disappeared. Histologically, the tumor was composed of spindle-shaped and oval cells in sarcoma, based on a moderate mitotic rate and cellularity. Immunohistochemically, the tumor was positive for CD34 and negative for keratin, α-smooth muscle actin, desmin, S100 protein, c-kit protein, and epithelial membrane antigen. Based on these findings, the tumor was diagnosed to be malignant SFT in the pelvic cavity.