Tsubasa Hiraki

Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: A pathognomonic histological feature and unique complication of SFTS

We report two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) with a high fatality rate in aged Japanese patients. Both cases were caused by a tick‐bite. The pathognomonic histological feature was necrotizing lymphadenitis of systemic lymphoid tissue with SFTS viruses and SFTSV‐RNA copies. Marked fungal infections were also observed in the lungs of both patients. Since cellular immune function may be suppressed in SFTS patients, physicians should be aware of possible fungal infections.

Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma.

Objectives The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features. Results The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002). Conclusions Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

Histological spectrum of angiofibroma of soft tissue: histological and genetic analysis of 13 cases

Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2–AHRR/AHRR–NCOA2 or GTF2I–NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis.

The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

Lymphangioleiomyomatosis in a Male.

We report a 17-year-old male with a histopathologic diagnosis of lymphangioleiomyomatosis after surgery for a pneumothorax. In general, lymphangioleiomyomatosis has been considered a female-specific disease. However, there are a few lymphangioleiomyomatosis cases reported in males, and our patient is the youngest case reported. Spontaneous pneumothorax occurs most commonly in males in their late teens and early twenties. Histopathologic diagnosis cannot always be performed in young males with pneumothorax. However, simple diagnosis should be avoided, and lymphangioleiomyomatosis should be considered as an underlying disease. This remarkable case provides new and valuable clinical insights into young male pneumothorax.

A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal.

Castleman’s disease in the retroperitoneal space mimicking a paraspinal schwannoma: a case report

BackgroundCastleman’s disease is a rare disease characterized by lymph node hyperplasia. Its occurrence in the retroperitoneal space has rarely been reported, making its preoperative diagnosis difficult. Here, we report a case of retroperitoneal Castleman’s disease, which radiologically resembled paraspinal schwannoma.Case presentationA 33-year-old Japanese man with epigastric discomfort underwent abdominal ultrasonic examination revealing a solid mass next to the right kidney. Computed tomography demonstrated a well-circumscribed mass with central calcification in the right psoas muscle. Because the mass presented a dumbbell-like shape extending to the intervertebral foramen, neurogenic tumor was suspected. Both iodine-123 metaiodobenzylguanidine and gallium-67 scintigraphies were negative in the mass, whereas thallium-201 mildly accumulated in the tumor, suggesting blood flow to the tumor. Positron emission tomography revealed accumulation of fluorine-18-2-fluoro-2-deoxy-d-glucose in the tumor at a standard uptake value of 4.7, whereas no other abnormal uptake suggestive of metastatic lesion was noted. On the basis of imaging studies, we mostly suspected paraspinal schwannoma, although malignancy was not completely excluded. Angiography showed feeding vessels from the right lumbar arteries, which were embolized with porous gelatin particles in order to reduce intraoperative bleeding. Surgical resection was performed using a retroperitoneal approach, which revealed the tumor in the swollen psoas muscle. Intraoperative pathological examination of a frozen section revealed no evidence of malignancy; thus, marginal excision of the tumor was performed. The tumor adhered tightly to surrounding muscle tissues, resulting in 940 g of intraoperative blood loss. The pathological examination demonstrated infiltration of lymphocytes surrounding small germinal centers with extensive capillary proliferation. Immunostaining revealed that proliferated lymphocytes were CD3-negative and CD79a-positive.ConclusionsAlthough a dumbbell-shaped mass in a paraspinal region is indicative of a schwannoma for orthopedic surgeons, the possibility of Castleman’s disease should be considered if a central low-signal area in fissured and a radial pattern is detected on computed tomography or magnetic resonance imaging. Appropriate preparation for massive bleeding during the treatment of Castleman’s disease, including angiography and embolization, would be helpful for performing surgical procedures safely.

The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.