Osamu Matsubara

Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis

SummaryTissue factor (TF) is an initiator of the extrinsic cascade of blood coagulation. Although recent studies have revealed a relationship between metastatic properties and TF expression in some neoplastic cells, the significance of TF in lung cancer, especially in non-small-cell lung cancer (NSCLC), is still unclear. In this study, TF was detected in NSCLC cell lines by functional study, Western blot analysis and immunocytochemical staining. TF levels in eight NSCLC cell lines were also quantitated by enzyme-linked immunosorbent assay (ELISA), and TF expression was evaluated in 55 specimens of surgically resected NSCLCs. NSCLC cell lines derived from metastatic lesions produced high levels of TF (48.3 ± 23.5 ng 10–6 cells, mean ± s.e.m.), whereas those derived from primary lesions produced low levels of TF (0.2 ± 0.1 ng 10–6 cells). Immunohistochemical studies disclosed significantly stronger staining for TF in cells from NSCLC patients with metastasis than in those without metastasis. Among the 28 patients with metastasis, ten were strongly positive, 16 were moderately positive and two were negative for TF. In contrast, among the 27 patients without metastasis, only two were strongly positive, 18 were moderately positive and seven were negative for TF. Therefore, malignant cells from patients with lung cancer produce various levels of TF, and TF may play an important role in the metastatic process.

Coronary artery lesions in Takayasu arteritis: Pathological considerations

SummaryThis communication reviews the clinical and pathological features of coronary artery lesions in Takayasu arteritis. The incidence of coronary artery involvement has been reported to be 9% to 10%, and is observed mainly in autopsy cases because coronary artery disease is usually not evident until the occurrence of angina pectoris or myocardial infarction, or after the onset of congestive heart failure. On the basis of pathological features, the following three types of coronary artery lesions can be distinguished: type 1, stenosis or occlusion of the coronary ostia and the proximal segments of the coronary arteries; type 2, diffuse or focal coronary arteritis, which may extend diffusely to all epicardial branches or may involve focal segments, so-called skip lesions; and type 3, coronary aneurysm. Most of the coronary artery lesions in Takayasu arteritis are of type 1. Narrowing of the coronary arteries is mainly due to the extension of the inflammatory processes of proliferation of the intima and contraction of the fibrotic media and adventitia from the ascending aorta. In some cases, coronary stenosis may be caused by coronary arteritis as skip lesions in Takayasu arteritis, but even in these cases the lesions have been reported to affect mainly the proximal segments of the coronary arteries. Diffuse lesions of the coronary artery and coronary artery aneurysm seem to be very rare in Takayasu arteritis. Other causes of coronary ostial stenosis, coronary arteritis and coronary artery aneurysm are also discussed.

Neoplastic angioendotheliosis. Immunohistochemical and electron microscopic findings in three cases

Three cases of neoplastic angioendotheliosis (NAE) presenting with central nervous system (CNS) disease but no skin lesions are described. The histogenesis of the neoplastic cells is discussed. Microscopic examination showed accumulation of neoplastic cells in the vascular system throughout the body and their extravascular proliferation in several organs. Electron microscopic and immunohistochemical studies revealed the presence of Weibel‐Palade bodies and factor VIII‐related antigen in intravascular and extravascular neoplastic cells in two of the three cases. In the first case the neoplastic cells did not have any T‐cell markers. However, in one case no specific markers were found in the neoplastic cells by electron microscopic, enzyme histochemical, or immunohistochemical examination. These findings, although supporting the endothelial origin of the neoplastic cells, indicate the need for further consideration of whether NAE is actually a single disease entity or several different diseases.

Deficiency of Interleukin-1 Receptor Antagonist Deteriorates Fatty Liver and Cholesterol Metabolism in Hypercholesterolemic Mice

Although the anti-inflammatory effect of interleukin-1 (IL-1) receptor antagonist (IL-1Ra) has been described, the contribution of this cytokine to cholesterol metabolism remains unclear. Our aim was to ascertain whether deficiency of IL-1Ra deteriorates cholesterol metabolism upon consumption of an atherogenic diet. IL-1Ra-deficient mice (IL-1Ra-/-) showed severe fatty liver and portal fibrosis containing many inflammatory cells following 20 weeks of an atherogenic diet when compared with wild type (WT) mice. Expectedly, the levels of total cholesterol in IL-1Ra-/- mice were significantly increased, and the start of lipid accumulation in liver was observed earlier when compared with WT mice. Real-time PCR analysis revealed that IL-1Ra-/- mice failed to induce mRNA expression of cholesterol 7α-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, with concurrent up-regulation of small heterodimer partner 1 mRNA expression. Indeed, IL-1Ra-/- mice showed markedly decreased bile acid excretion, which is elevated in WT mice to maintain cholesterol level under atherogenic diet feeding. Therefore, we conclude that the lack of IL-1Ra deteriorates cholesterol homeostasis under atherogenic diet-induced inflammation.

Angiosarcoma of the scalp : Report of two cases with fatal pulmonary complications and a review of Japanese autopsy registry data

Two cases of angiosarcoma of the scalp were reported. The patients were elderly men and died from pulmonary complications, including pneumothorax, pulmonary haemorrhage and pneumonia, associated with metastatic tumours in the lungs. The data recorded from 95 autopsies of patients with angiosarcoma in Japan during 1980–1984 were analyzed. According to the anatomical distribution of the primary tumour, the patients could be subdivided into a scalp group and non-scalp group. In both groups, the most common metastatic site was the lung. The patients of the scalp group had more frequent pulmonary complications such as pneumonia, haemothorax, atelectasis and pneumothorax, when compared with the patients of the non-scalp group. In particular, pneumothorax was observed only in the patients of angiosarcoma of the scalp. The results indicate that angiosarcoma of the scalp tends to metastasize to the lung, especially to the subpleural or surface pleural area, and these metastatic tumours are prone to necrosis, causing characteristic pulmonary complications.

MUCOEPIDERMOID CARCINOMA OF THE THYMIC REGION

A case of mucoepidermold carcinoma in thymus in a 59‐year‐old Japanese female is presented. She died of cardiac tamponade due to tumor invasion after a 5 years clinical course. At autopsy the main tumor was found in the thymic region with metastases to the sternum, regional lymph nodes, pericardial, and left pleural cavity. The mucoepidermold carcinoma might be probably originated from a hens egg‐sized cyst which was located in the upper posterior aspect of the tumor‐Involved thymus. No teratomatous components were present. The cyst was most likely to be of thymic or bronchogenic cyst origin, though it was not determined, in view of the lining with pseudo‐stratified ciliated columnar epithelium of the cystic wall and the surrounding with the thymic tissue outside. Moreover, there was thymic hyperplasia with germinal center that was compatible with SLE‐like symptoms in her past history and autoimmune nature of the autopsy findings of pulmonary fibrosis.

Is the epidermal growth factor receptor status in lung cancers reflected in clinicopathologic features

CONTEXT Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are molecular-targeted drugs that are innovatively effective for non-small cell lung carcinomas with EGFR mutations. Epidermal growth factor receptor is a transmembrane receptor forming dimers on ligand binding. These then stimulate signals by activating receptor autophosphorylation through tyrosine kinase activity. Autophosphorylation triggers intracellular pathways facilitating malignant conversion. The most clinically advanced EGFR inhibition strategies include small-molecule inhibition of the intracellular tyrosine kinase domain (gefitinib and erlotinib) and monoclonal antibody-mediated blockade of the extracellular ligand-binding domain (cetuximab). Lung cancers with EGFR mutations are prevalent among patients who are female, of Asian ethnicity, and nonsmokers; thus, they can obtain benefit from EGFR tyrosine kinase inhibitors. OBJECTIVE To survey histopathologic findings and examine correlations with EGFR mutations. We mainly focused on component cell types (hobnail, columnar, and polygonal) and presence or absence of bronchioloalveolar carcinoma elements and a micropapillary pattern. Although EGFR mutations can be detected by various methods, including polymerase chain reaction-Invader assay or direct sequencing, these are inconvenient. DATA SOURCES Review of the published literature. CONCLUSION Detailed pathologic examination showed significant genotype-phenotype correlations between EGFR mutations and presence of a bronchioloalveolar carcinoma component, a micropapillary pattern, and the hobnail cell type. We conclude that these characteristic histologic features are good predictors of EGFR mutations, and patients with these features might be good candidates for and could benefit from therapy with EGFR tyrosine kinase inhibitors.

Treated Wegener's granulomatosis : Distinctive pathological findings in the lungs of 20 patients and what they tell us about the natural history of the disease

Patients with an established diagnosis of Wegeners granulomatosis (WG) sometimes undergo lung biopsy when the disease does not behave in the expected manner. Treatment affects the tissue reaction. The microscopic recognition of partially treated disease is important, as the absence of expected lesions may lead to nonspecific diagnoses and inappropriate management. The appearance of treated disease over time may offer insight into its histogenesis and natural history. We correlated clinical features and pulmonary histology in 20 patients with WG after they had been treated with corticosteroids or cyclophosphamide or both. All patients had inflammatory or fibrotic pulmonary disease resulting from WG, but only 4 (20%) had macronodular necrosis typical of WG. Serum antineutrophil cytoplasmic antibody (ANCA) was elevated in all patients in whom it was measured. We divided the pathological findings into (1) vasculitis, (2) extravascular necrosis, (3) bronchiolitis, and (4) other lesions, and further divided them into (a) diagnostic for active disease, (b) suspicious for active disease, (c) suspicious for healing disease, (d) suspicious for residual disease, and (e) possible disease. Diagnostic or suspicious vascular lesions occurred in 15 patients (75%) and included granulomatous vasculitis, capillaritis or suspicious capillaritis, and neutrophilic vasculitis. Diagnostic or suspicious extravascular lesions occurred in 12 patients (60%) and included palisading granuloma, microabscess, macronodular pathergic necrosis, giant cell nodules, and micronodular scars. The giant cell nodules and nodular scars were an unusual healing pattern of palisading granulomas. Diagnostic bronchiolar lesions occurred in 1 patient (6%) and suspicious lesions in 13 patients (65%), including three novel patterns of bronchiolitis fibrosa (BF): (1) BF with giant cells, (2) BF with hemosiderin, and (3) BF with micronodular scars. Other features related to WG included diffuse alveolar damage, peculiar alveolar fibrin, interstitial fibrosis, pneumonitis resembling usual interstitial pneumonitis, and lipoid pneumonia. Classic necrotic nodules and vasculitis of WG should not be anticipated after therapy, but the diagnosis of pulmonary WG after treatment may be made if the effects of treatment on histology are considered. Changes in anticipated histology are found after therapy as short as 6 days. The histology typically has muted features. BF develops in most patients and may reflect a salutary effect of therapy. Palisading granuloma may convert to giant cell nodule or micronodular scar. Interstitial fibrosis is common, and pneumonitis resembling usual interstitial pneumonitis can develop. If only healing or residual disease is encountered, one should search further clinically and pathologically for active disease. Dampened inflammatory lesions represent smoldering disease that presumably needs additional therapy. Scarring presumably represents successfully treated but permanent disease.

Association of Sjögren's syndrome with pulmonary hypertension: report of two cases and review of the literature.

We report two autopsy cases of Sjögrens syndrome associated with pulmonary hypertension. The pulmonary muscular arteries of both cases showed concentric fibrocellular intimal proliferation, medial hypertrophy, and plexiform lesions. To determine the significance and pathogenesis of this rare association, we carried out morphometric and immunofluorescent studies and reviewed the seven similar cases reported in the literature. Depositions of immunoglobulin G, Clq, C3c, C4, and C5 were observed in the pulmonary arterial walls of both of our cases. Morphometric studies revealed increased medial thickness to radius ratios and intimal thickness to radius ratios of the pulmonary muscular arteries in both cases. Previously reported patients were all female, and those cases were frequently associated with Raynauds phenomenon. This report provides additional and convincing evidence for an association of Sjögrens syndrome and plexogenic pulmonary hypertension based on a detailed study of two cases and a review of the literature. The significance and pathogenesis of this association were examined, but not clarified. However, our studies add to the accumulating data suggesting a link between autoimmune diseases and chronic pulmonary hypertension.

Invasive fibrous tumor of the tracheobronchial tree: Clinical and pathologic study of seven cases

We describe seven cases of invasive fibrous tumors of the trachea and major bronchi with distinctive histologies and patterns of growth. The tumors are composed of proliferating fibroblasts and have moderate nuclear pleomorphism and low mitotic activity. The tumors bear some resemblance to inflammatory pseudotumor of the lung, fibrous histiocytoma, and fibromatosis, but differ from each of these entities. The tumors are neoplastic and invade down to or between plates of cartilage. Because of their proximal location, these tumors are usually amenable to sleeve resection. Recurrence is possible. Metastasis has not occurred. Distinction from more malignant mesenchymal tumors of the trachea and bronchus will prevent unnecessarily radical surgery.