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Twenty autopsy cases with 2009 pandemic influenza A (2009 H1N1) virus infection, performed between August 2009 and February 2010, were histopathologically analyzed. Hematoxylin-eosin staining, immunohistochemistry for type A influenza nucleoprotein antigen, and real-time reverse transcription-PCR assay for viral RNA were performed on formalin-fixed and paraffin-embedded specimens. In addition, the D222G amino acid substitution in influenza virus hemagglutinin, which binds to specific cell receptors, was analyzed in formalin-fixed and paraffin-embedded trachea and lung sections by direct sequencing of PCR-amplified products. There were several histopathological patterns in the lung according to the most remarkable findings in each case: acute diffuse alveolar damage (DAD) with a hyaline membrane (four cases), organized DAD (one case), acute massive intra-alveolar edema with variable degrees of hemorrhage (three cases), neutrophilic bronchopneumonia (five cases) and tracheobronchitis with limited histopathological changes in alveoli (four cases). In two cases, the main findings were due to preexisting disease. Influenza virus antigen was only detected in the respiratory tract in 10 cases by immunohistochemistry. The antigen was detected in type II pneumocytes (three cases) in the epithelial cells of the trachea, bronchi and glands (six cases), and in the epithelial cells in both of the above (one case). The four cases with acute DAD presented with antigen-positive type II pneumocytes. In one case, the D222G substitution was detected in the lung as a major sequence, although 222D was prominent in the trachea, suggesting that selection of the viral clones occurred in the respiratory tract. In five cases, the pathogenesis of 2009 H1N1 was confirmed to be viral infection in pneumocytes, which caused severe alveolar damage and fatal viral pneumonia. Further studies on both host and viral factors in autopsy or biopsy materials will be essential to elucidate the other pathogenic factors involved in influenza virus infection.

We report the pathological and virological findings of the first autopsy case of the 2009 pandemic influenza (A/H1N1pdm) virus infection in Japan. A man aged 33 years with chronic heart failure due to dilated cardiomyopathy, mild diabetes mellitus, atopic dermatitis, bronchial asthma, and obesity died of respiratory failure and multiple organ dysfunction syndrome. Macroscopic examination showed severe pulmonary edema and microscopically the lung sections showed very early exudative-stage diffuse alveolar damage (DAD). Immunohistochemistry revealed proliferation of the influenza (A/H1N1pdm) virus in alveolar epithelial cells, some of which expressed SAalpha2-3Gal on the cell surface. Influenza (A/H1N1pdm) virus genomic RNA and mRNA were also detected in alveolar epithelial cells. Real-time PCR revealed 723 copies/cell in the left lower lung section from which the influenza (A/H1N1pdm) virus was isolated. Electron microscopic analysis revealed filamentous viral particles in the lung tissue. The concentrations of various cytokines/chemokines in the serum and the autopsied lung tissue were measured. IL-2R, IL-6, IL-8, IL-10, IFN-alpha, MCP-1, and MIG levels were elevated in both. These findings indicated a case of viral pneumonia caused by influenza (A/H1N1pdm) virus infection, showing characteristic pathological findings of the early stage of DAD.

Although α1-antitrypsin (AAT) deficiency is one of the most common hereditary diseases and a recognized cause of emphysema in Caucasians, variants of this deficiency are extremely rare among Orientals. We present here a Japanese emphysema patient with the AAT deficiency variant originally identified as Siiyama. After an 8-year follow-up period, the patient suffered from repeated pulmonary Pseudomonas aeruginosa infection for 4 years. He died suddenly of massive pulmonary hemorrhage. The pathologic examination revealed a necrotic hematoma in the right S10 lobe, which exhibited pneumonia due to cytomegalovirus (CMV) infection. Pulmonary hemorrhage due to CMV can occur and be fatal in patients with emphysema and AAT deficiency.

A 22-year-old man with acute lymphoblastic leukemia underwent allogeneic stem cell transplantation (allo-SCT) twice, then underwent allo-SCT a third time due to relapse. On day 27, he developed acute respiratory distress, and bilateral interstitial infiltrates were noted on CT images. Despite receiving intensive treatment, the patient died on day 32 from progressive respiratory failure. An autopsy revealed evidence of diffuse alveolar damage caused by the genus Toxoplasma. At present, toxoplasmosis is considered to be a rare infectious complication in Japan. However, the actual incidence of toxoplasmosis may be higher than currently believed due to a lack of suspicion of the diagnosis in patients, difficulty in making a diagnosis and low autopsy rates.

A 67-year-old man was referred to our clinic with a complaint of macroscopic hematuria. He had been treated for schizophrenia in a psychology ward. Computed tomography (CT) scan revealed a left renal tumor 7 cm in size, well enhanced in early phase. Doppler ultrasonography indicated hypervascular left renal tumor. Laparoscopic radical left nephrectomy was performed under the diagnosis ofrenal cancer. Histopathlogical results showed a renal solitary fibrous tumor (SFT) with a hemangiopericytoma-like pattern. Renal SFT is an uncommon tumor. The present case is the 11th reported case of SFT with hemangiopericytoma-like pattern in the Japanese literature.

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.

Chronic granulomatous disease (CGD) is based on the dysfunction of phagocytes and characterized by a comparatively uniform granulomatous lesion caused by organisms which do not produce hydrogen peroxide and which are catalase-positive. This report describes two autopsy cases in children, a nine year-two month-old boy and a ten month-old girl, with the clinical manifestations and autopsy findings of CGD and a brief review of all autopsy cases consistent with CGD reported in Japan. In these cases, in addition to the usual CGD lesions, there was a markedly different type of granuloma due to Aspergillus sp., which consisted of multinuclear giant cells alone, or a caseous center surrounded by giant cells. This peculiar type of aspergillosis may correspond to a primary infection, described as pseudotuberculosis aspergillina. It appears that in some CGD patients, macrophages may function normally and sometimes be more activated by these infections than in the normal body. The histochemical and electron microscopic examination of the present cases and a review of the previous cases suggest that the yellowish brown pigment found seems to resemble a ceroid. It is a product of the degradation of leukocytes and tissue elements with subsequent accumulation in phagocytic histiocytes and is not necessarily peculiar to CGD.

Six cases of synovial sarcoma were examined histochemically in order to clarify the components of mucosubstances in the tumor tissues. The tumors were classified into 1) monophasic type, 2) predominantly monophasic type with focal biphasic differentiation, and 3) biphasic type. The former two groups and sarcomatous areas in the biphasic tumors contained various amounts of hyaluronic acid, chondroitin sulfate, and, in some cases, heparitin sulfate. By contrast, the epithelioid regions in the biphasic-type tumors had periodic acid-Schiff-positive glycoproteins which contained various amounts of sialic acid, in addition to hyaluronic acid and chondroitin sulfate. The significance of the presence of glycoproteins in the mesenchymal tumors is emphasized. It seems likely that the synovial sarcomas contain various kinds of mucosubstances and that sensitivity to hyaluronidase treatment is not necessarily the diagnostic criterion of synovial sarcoma.