Yasuyoshi Yoshii

Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences.

Expression of thrombomodulin (TM) in atherosclerotic lesions of the human aorta (8 cases of diffuse intimal thickening, 4 fatty streaks, 11 atheromatous plaques, and 5 fibrous plaques) as well as in undiseased aortas of 5 infants obtained at autopsy was studied immunohistochemically using a novel polyclonal antibody against human TM. TM was expressed in intimal smooth muscle cells (SMC) besides endothelial cells and foamy macrophages in almost all patients (26/28). In addition, medial SMC in adult cases over 27 years of age expressed TM. In young adults with diffuse intimal thickening under 26 years of age, medial SMC showed no TM expression whereas intimal SMC did show it. Both intimal and medial SMC in infants showed no TM expression. An immunofluorescence method showed TM expression in cultured adult human SMC. These findings indicate that TM expression in SMC may depend on patient age as well as lesion type of atherosclerosis.

Nonalcoholic steatohepatitis-related cirrhosis with subacute liver failure: an autopsy case.

To the Editor: Nonalcoholic steatohepatitis (NASH), so named in 1980 by Ludwig et al (1), is part of the spectrum of nonalcoholic fatty liver diseases and has the same pathological findings as alcoholic hepatitis. It occurs frequently in obese middle-aged females, in type 2 diabetes, and in jejunoileal bypass surgery as a treatment for obesity (1, 2). Previously considered to be a benign nonprogressive condition, NASH can progress to advanced fibrosis/cirrohosis (3) and, rarely, to liver failure (4). Here we present a case of NASH related cirrhosis with a fatal outcome. A 76-year-old female (body mass index of 25.2 kg/m 2, overweight) underwent a laparoscopic cholecystectomy because of cholelithiasis at age 71. At that time, blood tests were normal as was the gross appearance of the liver. She consulted the hospital complaining of having suffered general fatigue for two months. Liver dysfunction (bilirubin 5.2 g/dl, AST 356 IU/liter, ALT 85 IU/liter, and prothrombin time 49%) was found. Fasting glucose was normal. There was no infection of hepatitic viruses such as hepatitis A, B, or C. No anti-nuclear or anti-mitochondrial antibodies were present. Serum ceruloplasmin was normal. Questioning of the patient and her relatives revealed that she had little exposure to alcohol and took no drugs. Fresh frozen plasma infusion, plasma exchange, adsorption of bilirubin, and extracorporeal ultrafiltration method therapy were performed. However, her condition deteriorated, and she developed encephalopathy with worsening of her liver function (albumin 2.7 g/dl, bilirubin, 14.7 mg/dl, AST 166 IU/liter, ALT 127 IU/liter, and prothrombin time 32%). In spite of further treatment, she died of liver failure 4 months from the onset of clinical symptoms. An autopsy was performed. The patient had jaundice, ascites (80 ml), and the liver weighed 600 g. Histologically, the liver consisted of pseudonodules, proliferated ducts and fibrous septum. Macrovesicular steatosis was present in about 30% of the hepatocytes (Figure 1A). Lymphocytes and neutrophils were infiltrated within the nodules and septum. Mallory bodies with neutrophilic infiltration and hepatocyte ballooning were frequently observed (Figure 1B). Hepatocyte necrosis and bile stasis were also seen. Berlin blue staining revealed that iron deposition was present only in Kupffer cells, but not in hepatocytes. α-smooth muscle actin (α-SMA) -positive spindle cells (Ito cells) (5) proliferated and were distributed irregularly within nodules (Figure 1C). Esophageal varices were present, and the spleen was not enlarged (50 g). The patient presented with general fatigue and liver dysfunction (hypoalbuminemia, hyperbilirubinemia, and prolonged prothrombin time), and developed hepatic encephalopathy about 3 months after the onset of symptoms. Although intensive treatment was undertaken, she died of liver failure. Postmortem examination of the liver showed macrovesicular steatosis, hepatocyte ballooning, frequent Mallory bodies, and inflammation including neutrophils, which are compatible with NASH or an alcoholic liver disease (6, 7). Serological evidence of viral hepatitis, markers of autoimmunity, reduced ceruloplasmin, and iron deposition in the hepatocytes were absent, and she had consumed very little alcohol. From these findings, liver cirrhosis in our patient was diagnosed as NASH-related. NASH-related cirrhosis with subacute liver failure is rare (4). Recently, Caldwell and Hespenheide reported 5 such cases among 2380 liver disease cases (8). Among them, 4 died of liver failure over a period of 4–16 weeks from the onset of symptoms. These patients had no history of liver disease before the appearance of liver failure. Our patient had both normal blood tests and gross appearance of the liver at age 71, and she seemed to have progressed to cirrhosis over 5 years but without exhibiting any clinical symptoms. NASH is now believed to be the commonest cause of asymptomatic patients presenting to general hepatology practice with persistently abnormal liver blood tests (9). When liver dysfunction with unknown etiology occurs, the possibility of NASH should be considered. Our case demonstrates that NASH-related cirrhosis can progress to liver failure. Recently steatohepatitis has been proposed as a tale of two hits, the first hit being steatosis, and the second a source of oxidative stress capable of initiating significant lipid peroxidation (10). The aldehyde products of lipid peroxidation are capable of activating hepatic Ito cells, inducing fibrosis, cross-linking cytokeratins to form Mallory bodies, and stimulating neutrophilic chemotaxis (10). In nonalcoholic fatty liver diseases, poor outcomes are more frequent in patiens in whom biopsies show ballooning degeneration and Mallory bodies or fibrosis (11). Our case revealed these liver cell degenerations with inflammation and the proliferation of Ito cells. A high degrees of liver cell damage and subsequent fibrosis may lead to liver failure in some NASH cases.

Leiomyosarcoma arising from soft tissue tumor of the mediastinum

 The occurrence of a leiomyosarcoma (LMS) in soft tissue of the mediastinum is rare. We report a 60-year-old woman with an LMS in mediastinal soft tissue who died 8 months after surgical removal. Pathological, immunohistochemical, and electron microscopic features of this rare tumor are described.

Synovial sarcoma arising from the pleura: a case report with ultrastructural and immunohistological studies.

 Synovial sarcoma commonly occurs in the para-articular regions of the extremities, and rarely in the pleura. We report a 46-year-old woman with primary synovial sarcoma of the pleura. She was admitted with a complaint of left-sided chest pain and exertional dyspnea. She had previously undergone two operations for pleural neoplasm, at the ages of 33 and 36 years. A computed tomography scan revealed an expanded mass in the left thoracic cavity, involving the surrounding tissue. Macroscopic findings demonstrated a 25 × 25 × 15-cm grayish-white mass with hemorrhage beneath the pleura. Both epithelial and spindle cells were observed microscopically. Ultrastructural microscopy of the epithelioid cells demonstrated short, blunt microvilli on the luminal surface, and desmosomes between the neoplastic cells. Immunohistochemically, the tumor cells of the epithelial component were positive for embryonal membrane antigen (EMA), carcinoembryonic antigen (CEA), human mesothelial cells (HBME)-1, and cytokeratin, and the spindle cells were positive for vimentin. These findings led us to a diagnosis of primary synovial sarcoma of the pleura. She had no evidence of recurrence or metastasis after the third operation.

Case of primary malignant hemangiopericytoma of the heart expressing basement membrane-degradable enzymes

An echocardiogram demonstrated a large tumor in the left atrium of a 47‐year‐old woman with sudden heart failure. Emergent cardiotomy showed that the tumor arose from the left atrial wall, and almost entirely occupied the left atrium. Grossly, the tumor had partly undergone necrosis. Histologically, the tumor consisted predominantly of round to polygonal cells with ill‐defined cell borders surrounding ‘stag horn’‐shaped blood vessels. Mitosis was frequently seen with abnormal mitotic figures. Immunohistochemically, the tumor cells diffusely expressed vimentin and focally expressed factor XIIIa and human leukocyte antigen‐DR. A few tumor cells expressed S‐100 protein or α‐smooth muscle actin. Histopathological diagnosis was malignant hemangiopericytoma of the left atrium. Most tumor cells expressed matrix metalloproteinase (MMP)‐2 and MMP‐3, and several cells expressed MMP‐9, all of which are capable of degrading a major component of basement membrane (i.e. type IV collagen). Furthermore, tumor cells expressed membrane type 1 MMP and tissue inhibitor of metalloproteinase‐2, both of which are required for activation of proMMP‐2. Fourteen months after the surgical removal, she died of systemic recurrent tumors.

Anaplastic large-cell lymphoma (Ki-1 lymphoma) : ultrastructural and immunohistochemical studies

 We report an autopsy case of a malignant neutrophil-rich anaplastic large cell lymphoma (ALCL), which was reactive to the monoclonal antibody Ki-1 (CD30). This subtype of Ki-1 ALCL containing many neutrophils was named by Mann and colleagues in 1995, and its clinical and pathological characteristics have not been well described. In our case, the patient died 2 months after he first noticed an abdominal skin tumor. It was difficult to make the exact diagnosis of malignant lymphoma because the histological examination showed very poorly differentiated tumor cells. Ultrastructural observations revealed nuclei with convoluted contours and, sometimes, deep indentations, which suggested ALCL. Immunohistologically, most neoplastic cells were reactive with Ki-1 (CD30), leukocyte common antigen (LCA), and CD45RO (UCHL-1), and we confirmed Ki-1 ALCL. When we encounter poorly differentiated tumors on light microscopy, we should perform immunohistochemistry for hematological markers, such as LCA and Ki-1.

Waldenström's macroglobulinemia: report of an autopsy case presenting with a pulmonary manifestation

An autopsy case of Waldenströms macroglobulinemia is reported, in whom an abnormal pulmonary shadow had already existed 2 years before the diagnosis of the disease and was proved to be pulmonary involvement. Immunoelectrophoresis demonstrated a monoclonal increase in immunoglobulin M with kappa light chain. A chest X-ray film showed a reticulo-nodular shadow in the right lower lobe of the lung. A bronchial biopsy specimen revealed a diffuse and dense lymphocytic infiltration. Bone marrow aspirate revealed no remarkable change except for a slight increase in plasma cells (1.7%) and an appearance of atypical lymphocytes (0.5%). At autopsy, more than half of the right lower lobe of the lung was occupied by a pale whitish, viscid and glossy tumour mass. Heptosplenomegaly and lymph node enlargement were not observed. Histological findings of the tumour tissue were similar to those of the biopsy specimen. Lymphocytic infiltration was observed also in the liver, kidneys, spleen, bone marrow and lymph nodes, but was of minor degree. Other reported cases of Waldenströms macroglobulinemia accompanied by pulmonary involvement are reviewed.