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Human intestinal spirochetosis (HIS), one of the zoonoses, is caused by colonization by Brachyspira species bacteria within the large intestine. Histologic diagnosis of HIS is usually established by finding "fringes" on the colonic surface epithelium in biopsy specimens. However, its histologic characteristics, especially beneath the colonic mucosa, have not been elucidated. The present study was designed to examine the histologic characteristics of HIS in operatively resected specimens. We reviewed operatively resected (colectomy or appendectomy) specimens obtained in six consecutive years at a single medical center. HIS was diagnosed histologically by finding "fringes". Immunohistochemical study using anti-Treponema pallidum antibody, which cross-reacts with Brachyspira, was additionally performed. A total of 848 (M:F = 477:371; median age, 59 years; 12-94 years) colectomy and/or appendectomy cases were examined, and the seven cases (0.8%) diagnosed as having HIS were all male (1.5% of male cases). Four HIS cases (0.8% of 508 colectomy cases (1.4% of 285 male-cases)) were colectomy cases with cancers, and the other three (0.9% of 340 appendectomy cases (1.6% of 192 male-cases)) were appendectomy cases for acute appendicitis. Our study revealed (1) a heterogeneous distribution of diagnostically important "fringes" within the large intestine, (2) an ileal presence of Brachyspira, (3) superficial location of HIS-related findings among anatomical wall layers, and (4) the presence of Brachyspira or its derivatives within macrophages in the lamina propria and immune apparatus (lymphoid follicles in superficial wall structures (lamina propria or submucosa) and lymph nodes). Investigation using operatively resected specimens might help elucidate the characteristics of HIS. Brachyspira may have immunogenicity in humans.

Tracheobronchial schwannomas are rare diseases. Common signs and symptoms of this tumor include cough, wheezing, and dyspnea. In contrast, pneumothorax is an exceptional presentation. This study reports the first case of bronchial schwannoma presenting with pneumothorax. A 79-year-old woman was diagnosed with pneumothorax by chest radiography. Chest computed tomography unexpectedly revealed a tumor occluding the right main bronchus. Following the pathological diagnosis of bronchial schwannoma, the patient underwent thoracoscopic tumor enucleation. The airway lumens are consequently secured postoperatively. We reviewed the literature and discussed the mechanisms and treatment options for bronchial benign tumor-associated pneumothorax. Pneumothorax should be aware of a rare presentation of non-malignant tracheobronchial tumors.

We describe a rare case of meningeal carcinomatosis (MC) in a 66-year-old man who presented with bilateral deafness and vertigo, initially presumed to be neurofibromatosis type-2. Brain magnetic resonance imaging (MRI) of the patient revealed bilateral gadolinium enhanced masses at the cerebellopontine angle. However, multiple central nervous system symptoms, including loss of consciousness, gradually appeared. He had a history of gastric cancer; therefore, a lumbar puncture was performed. Cytological examination of the cerebrospinal fluid confirmed the presence of adenocarcinoma cells. The general condition of this patient worsened, and he died 46 days after the first onset of hearing loss. An autopsy was performed, and multiple infiltrations of adenocarcinoma cells in the brain were confirmed, though undetected by MRI. The prognosis of MC is extremely poor; therefore, rapid diagnosis is important to prevent mortality. Retrospectively, a lumbar puncture could have been conducted earlier to identify MC, especially in consideration of the clinical history of this patient.

Spontaneous regression of sarcoma is exceedingly rare. A 62-year-old male presented with myxofibrosarcoma of the thigh which regressed after open biopsy. Treatment strategy for this condition is not well-documented in the literature. In this report, we describe the case of a spontaneously regressed myxofibrosarcoma successfully treated by resection where the extent of the tumor was determined from the initial MRI. This case demonstrates that myxofibrosarcoma has the potential to regress spontaneously, and astute awareness of this phenomenon is necessary for appropriate management of this condition.

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Pulmonary capillary hemangiomatosis (PCH) is a rare disease that causes uncontrollable proliferation of pulmonary capillaries. We experienced a 52-year-old man who was diagnosed with LVNC about 8 years previously who subsequently died of heart failure. The major autopsy findings were enlargement of the heart with prominent trabeculations and deep intertrabecular recesses in the apical and middle regions of the left ventricular wall. The mean ratio of noncompacted to compacted layers was 2.4. In the lung, thickened alveolar walls with numerous pulmonary capillaries were evident, findings very similar to PCH. PCH-like lesions and LVNC may have coexisted coincidentally, and both, or either of them, may have contributed to the development of his pulmonary hypertension.

The current study aimed to investigate the plausible histopathological factors that affect the detectability of prostate cancers on multiparametric magnetic resonance imaging (MP-MRI). This retrospective study included 59 consecutive patients who had undergone MP-MRI and subsequent radical prostatectomy. The cases were standardized according to the tumor size ranging from 10 to 20 mm on the final pathological diagnosis. Histopathological review and semi-automated imaging analysis were performed to evaluate the relative area fractions of the histological components, including cancer cells, stroma, and luminal spaces. Among the 59 prostatectomy specimens, no case showed two or more foci of cancer that matched the size criteria. Of the 59 lesions, 35 were MRI-detectable [Prostate Imaging Reporting and Data System (PIRADS) score of 3 or greater] and 24 were MRI-undetectable (PIRADS score of 2 or less). No significant differences were observed in Gleason Grade Group, percentage of Gleason pattern 4, and predominant subtype of Gleason pattern 4 between MRI-detectable and MRI-undetectable cancers. On the other hand, significantly higher mean area fraction of cancer cells (60.9% vs. 42.7%, P

Human intestinal spirochetosis (HIS) is a colorectal infection by Brachyspira species of spiral bacteria. Immunohistochemical cross-reaction to an antibody for Treponema pallidum aids its histologic diagnosis. This study's aim was to analyze the immunohistochemical characteristics of HIS. In this analysis, on 223 specimens from 83 HIS cases, we focused on so-called fringe formation (a histologic hallmark of HIS), spiral organisms within mucus or within crypts, and strong immunopositive materials in the mucosa, together with their location and the types of lesions. Fringe formation was found in 81.6% of all specimens and spiral organisms within mucus or within crypts in 97.3% and 57.0%, respectively. Strong immunopositive materials were observed in the surface epithelial layer in 87.9%, in the subepithelial layer in 94.6%, and in deeper mucosa in 2.2% of all specimens. The positive rates in conventional adenomas (24.0%, n = 146) and hyperplastic nodules (100%, n = 17) were each different from that found in inflammation (70.8%, n = 24), and spiral organisms were seen more frequently in the right-side large intestine than in the left (within mucus, 100%, n = 104 versus 95.0%, n = 119; within crypts, 65.4%, n = 104 versus 49.6%, n = 119). Thus, immunohistochemistry was effective not only in supporting the diagnosis of HIS but also in highlighting spiral organisms within mucus or crypts that were invisible in routine histology. Possibly, these spiral organisms may spread throughout the entire large intestine, although there is a potential problem with antibody specificity.

Background Recently, claudin-4 (CL4) immunocytochemistry was reported to be useful for differential diagnosis in effusion cytology. We wondered whether CL4 might be useful for “single-shot” identification of metastatic carcinoma. The purpose of this study was to evaluate the usefulness of CL4 in effusion cytology. Methods In total, 266 cases (169 metastatic carcinomas, eight malignant mesotheliomas, and 89 reactive mesothelial cells) were selected. Immunocytochemical examinations of cell-block sections were performed for CL4, Ber-EP4, and MOC-31. We used an arbitrary 4-tiered scale based on both staining intensity and positive-cell percentage among all target cells, and calculated a staining index score (sum of the above two scores). Results In a ROC-curve analysis, higher area-under-curve values were found for CL4 than for Ber-EP4 or MOC-31 (0.982, 0.942, and 0.926, respectively). Conclusions Since CL4 exhibited similar or superior usefulness to Ber-EP4 and MOC-31, it could become the first choice for the above differential diagnosis in effusion cytology. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Aims Peritoneal malignant mesothelioma (PMM) is an uncommon tumour, accounting for only 7–9% of all mesotheliomas in Japan. Differential diagnosis between PMM and primary peritoneal serous carcinoma (PPSC), a high-grade serous carcinoma, may be difficult, and separating reactive mesothelial hyperplasia (RMH) from PMM can be even more challenging. Methods To help differentiate PMM from PPSC and RMH, we used immunohistochemistry to examine mesothelial-associated markers (calretinin, AE1/AE3, CK5/6, CAM5.2, D2-40, WT-1, HBME1, thrombomodulin), adenocarcinoma-associated markers (CEA, BerEP4, MOC31, ER (estrogen receptor), PgR, TTF-1, Claudin-4, Pax8), and malignant-related and benign-related markers (epithelial membrane antigen (EMA), desmin, GLUT-1, CD146 and IMP3), and FISH to examine for homozygous deletion of 9p21. We used formalin-fixed, paraffin-embedded blocks from 22 PMMs (M:F=18:4; subtypes: 16 epithelioid, 6 biphasic), 11 PPSCs and 23 RMHs. Results Seventeen of the mesotheliomas (four PMM from women) were classified as diffuse, while five were localised. Calretinin was 91% positive in PMM, but negative in PPSC (specificity, 100%). BerEP4, Claudin-4 and PAX8 were all 100% positive in PPSC (specificities, 100%, 95% and 95%, respectively, for excluding PMM). For distinguishing PMM and RMH, sensitivity for EMA in mesothelioma was 68%, while for IMP3 and GLUT-1 it was 64% and 50%, respectively, all with high specificities. FISH analysis revealed homozygous deletion of the 9p21 locus in 11/13 PMMs, but in 0/11 RMHs. Conclusions Calretinin and BerEP4 may be the best positive markers for differentiating PMM from PPSC. EMA, in combination with IMP3 and desmin, is useful, and homozygous deletion of 9p21 may be helpful, for differentiating PMM from RMH.

By allelotyping analysis, we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma, then to embryonal carcinoma in mixed-type testicular germ cell tumors (TGCTs), and detected that loss of heterozygosity events in seminoma components in mixed tumors were more frequent than those in pure seminomas. To elucidate a role of chromosomal instability in the progression of non-seminomatous germ cell tumor (NSGCT), we performed fluorescence in situ hybridization with centromeric probes for chromosomes 1, 7, 8, 12, 17, and X on a cohort of 52 TGCT cases with 103 histologically distinct components: 39 GCNIS lesions (16 and 23 in tumors with and without NSGCT components, respectively), 39 seminomas (27 as pure seminomas and 12 in mixed tumors), and 25 embryonal carcinomas. On a total component basis, both the mean copy number per tumor cell nucleus and the deviations from the modal number of all chromosomes examined significantly increased from GCNIS to seminoma, then to embryonal carcinoma with few exceptions. Seminoma components in mixed tumors showed a significantly greater extent of chromosomal instability in chromosomes 8 and 12 than pure seminomas, whereas no statistically significant difference was observed between GCNIS lesions with and without NSGCT components. These results suggest that not only aneuploidy, but also the cell-to-cell variation of chromosomal number is a sensitive indicator of chromosomal instability and would be implicated in the progression of NSGCT.

Using analysis of allelic loss (loss of heterozygosity [LOH]), we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma and then to embryonal carcinoma in mixed-type testicular germ cell tumors. To identify the genetic backgrounds related to the progression of nonseminomatous germ cell tumor, patterns of LOH were studied in seminoma components in mixed tumors (18 cases), pure seminomas (20 cases), and coexisting GCNIS lesions. Each tumor was assessed for LOH at 22 polymorphic loci located on 12 chromosomal arms: 3q, 5q, 6p, 9p, 10q, 11p, 12p, 12q, 13q, 17p, 17q, and 18q. For all informative loci, the frequency of LOH in seminoma components in mixed tumors was significantly higher than that in pure seminomas (32% [96/302 loci] versus 19% [60/323 loci], P .0001). The frequency of LOH in GCNIS lesions was not significantly different between the 2 tumor groups. The frequencies of LOH at chromosomes 6p and 10q were significantly higher in seminoma components in mixed tumors than in pure seminomas (P = .020 and P = .0041, respectively). Immunohistochemical analysis demonstrated a close association between the allelic status of the 10q23 locus and levels of phosphatase and tensin homolog deleted from chromosome 10 protein expression in seminoma (P = .00051). These data indicate that the seminoma, which has a potential to progress to nonseminomatous germ cell tumor, already exhibits several genetic changes including allelic losses of 6p and 10q, unlike pure seminoma.

Little is known about the association between the atypical adenomatous hyperplasia (AAH)-adenocarcinoma in situ sequence of the lung and endoplasmic reticulum-stress responders such as ATF6, XBP1, and GRP78. Using stored tissues, we examined (i) the percentage of a splicing form (active form) of XBP1 messenger RNA in normal lung tissue (NLT) and adenocarcinoma (ACA; using reverse-transcription polymerase chain reaction); (ii) ATF6 and GRP78 protein expressions in NLT and ACA (using Western blotting analysis); (iii) ATF6, XBP1, and GRP78 protein expressions in NLT, AAH, and ACA, including some adenocarcinoma in situ (using immunohistochemistry); and (iv) the incidence of nuclear translocation of the 3 proteins in these lesions. The percentage of the splicing form of XBP1 messenger RNA showed a borderline difference between NLT and ACA (P = .068). In the Western blotting analysis, the nuclear fractions of ATF6 (including the active form) and GRP78 proteins were higher in ACA than in NLT. In the immunohistochemistry, the values obtained for the incidence of the nuclear translocation of ATF6, XBP1, and GRP78 proteins were as follows, respectively: 13.3%, 2.2%, and 0.5% in low-grade AAH; 37.9%, 2.3%, and 2.2% in high-grade AAH; and 47.2%, 10.6%, and 4.4% in ACA. A significant difference was detected between low-grade AAH and ACA for ATF6. In terms of nuclear translocation, high-grade AAH seemed intermediate between low-grade AAH and ACA. These results support endoplasmic reticulum-stress responses, such as nuclear translocation of these 3 proteins (including their active forms), being in parallel with the progression of the adenoma-carcinoma sequence in the lung.

Background Podocyte phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic adult membranous nephropathy (MN). Histological PLA2R staining in the renal tissue has proven to be useful for the detection of idiopathic MN. However, glomerular PLA2R deposits have also been recently observed in several patients with secondary MN, such as hepatitis B virus-associated, hepatitis C virus-associated, and neoplasm-associated MN. Certain inflammatory environments have been suggested to lead to abnormal expression of PLA2R epitopes, with the resulting production of PLA2R autoantibodies. Case presentation We report two patients diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with MN-lesions, in whom ANCA titers for myeloperoxidase (MPO) were persistently positive. The first patient was a 52-years-old man who presented with interstitial pneumonitis. Microscopic hematuria and proteinuria were found when the interstitial pneumonitis became more severe. Renal biopsy findings yielded a diagnosis of ANCA-associated glomerulonephritis (mixed class) with MN-lesions. The second patient was a 63-years-old woman who had been treated for relapsing polychondritis. Her renal tissue showed evidence of focal ANCA-associated glomerulonephritis with MN-lesions. Interestingly, both MPO and PLA2R were detected in the glomerular subepithelial deposits of both patients. Immunoglobulin G (IgG) 1 and IgG2 were positive in the glomeruli of patient 2, and all subclasses of IgGs were positive in patient 1. Conclusion The present cases suggest that ANCA-associated glomerulonephritis could expose PLA2R, leading to the development of MN-lesions.

Gastrointestinal massive arterial hemorrhage is difficult to stop endoscopically, especially from a duodenal ulcer (DU), because of the anatomically narrow lumen. Here we report a rare case of small pancreatic cancer-induced lethal hemorrhagic DU. The 69-year-old patient was transferred due to massive hematemesis, hypotension and loss of consciousness. Emergency upper endoscopy revealed a DU with active bleeding from an unclear hemorrhagic spot, which stopped transiently by itself. Subsequently he began to vomit blood again and angiography showed extravasation from the gastroduodenal artery (GDA). Hemostasis by transcatheter arterial embolization (TAE) was achieved but the patient unfortunately died soon after because of hemorrhagic shock (10 h after his first hematemesis). The autopsy revealed a small pancreatic cancer (poorly differentiated adenocarcinoma, 10 × 25 mm in size) infiltrating into one-half of the penetrating DU with a nearby ruptured GDA wall, suggesting that the DU was caused by the pancreatic cancer. Our 7-year analysis of emergency endoscopies in our department for upper gastrointestinal bleeding revealed that TAE was performed in more cases of duodenal hemorrhage (5.7 %) than stomach hemorrhage (1.8 %), showing the difficulty in stopping hemorrhage from DU endoscopically. This case raises the possibility that intractable lethal hemorrhagic DU could be caused by a very small pancreatic tumor.

Background: The introduction of new therapies has made it important to differentiate between adenocarcinoma and squamous cell carcinoma. To allow the use of various immunocytochemical stains on limited materials, we tried transferring cells from a given smear to multiple slides. Using touch-preparation samples of 215 surgically resected non-small cell lung carcinomas of confirmed histologic classification (adenocarcinoma,n = 101; squamous cell carcinoma,n = 114), we performed immunocytochemistry for thyroid transcription factor-1, napsin A, p40, p63, CK5/6 and desmocollin-3, and compared cytologic staining results with the corresponding resection. Methods: We examined: (a) the expressions of the above 6 antibodies on cells transferred from touch imprints of resected specimens, the extent of staining being considered positive if more than 5% of the area was stained, and (b) the sensitivity, specificity, positive predictive value and negative predictive value for each antibody. Results: The histologic corresponding rate with Papanicolaou staining was only 73%. Regarding the differentiation of adenocarcinoma from squamous cell carcinoma, the sensitivity and specificity for napsin A in adenocarcinoma were 80 and 97%, respectively, while those for p40 in squamous cell carcinoma were 84 and 98%, respectively. Conclusion: The immunocytochemical expressions of napsin A and p40 in imprint cytology seem to be of great utility for the accurate histological differentiation of lung cancers.

Primary nonsecretory plasma cell leukemia (PCL) is an extremely rare type of multiple myeloma. Here, we report a case of nonsecretory PCL with no previous history of multiple myeloma. The case exhibited extremely low levels of serum immunoglobulin and light chain, no detectable serum M-protein or free light chain restriction, no urine BJP, and no cytoplasmic light chain expression in flow cytometry. In fluorescence in situ hybridization, tumor cells exhibited fusion genes for IgH/BCL1 and IgH/cMyc, disappearance of the p53 signal, and a split signal for IgK(2p11), but no split signal for IgL (22q11). Therefore, we diagnosed primary nonsecretory PCL with multiple chromosomal abnormalities.

Most patients with human intestinal spirochetosis (HIS; a colorectal bacterial infection caused by Brachyspira species) seem asymptomatic, and its pathogenicity remains unclear. Recently, alterations in mucin expression were reported in animal Brachyspira infection. The present question was "Is mucin expression altered in HIS?" Using antibodies for MUCs 1, 2, 4, 5AC, and 6, we immunohistochemically compared 215 specimens from 83 histology-confirmed HIS cases with 106 specimens from 26 non-HIS cases. Positive staining (which included even focal positive staining) was rated "high (+)" or "low (+)." Results were analyzed for 4 categories of lesions, and associations between MUC expression and spirochetal presence were also analyzed. In the "specimens without polyps or adenocarcinoma" category, high (+) MUC2 positivity was more frequent in HIS than in control. In the hyperplasia/serrated polyp category, in HIS (versus control), the MUC5AC positivity rate was lower, whereas high (+) MUC4 positivity was more frequent. In the conventional adenoma category, in HIS (versus control), the MUC1 positivity rate was lower, whereas both high (+) MUC2 positivity and high (+) MUC5AC positivity were less frequent. In the adenocarcinoma category, high (+) MUC2 positivity was more frequent in HIS than in control. Among the above mucins, only MUC1 positivity was significantly associated with an absence of the so-called fringe formation, an absence of spiral organisms within mucus, and an absence of strong immunopositive materials within the epithelial layer and within the subepithelial layer. The results suggest that Brachyspira infection or a related change in the microbiome may alter the large intestine mucin expression profile in humans.

Massive hemolysis due to passenger lymphocyte syndrome (PLS) is rare after peripheral blood stem-cell (PBSC) transplantation with a minor ABO mismatch. We present, in a 16-year-old boy (group A Rh+), PLS with hemophagocytic syndrome (HPS) after PBSC transplantation from his HLA (human leukocyte antigens)-matched biological sister (group O Rh+). Mild-to-moderate hemolysis was evident from day +11 to day +15 after transplantation. HPS was diagnosed by bone marrow examination on day +16, while antibodies against the recipient's red blood cell antigens were detected on days +15 and +27. This hemolysis may have been due to PLS with HPS. Therefore, measurement of antibodies may provide a useful hallmark of immune hemolysis.

Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a ×20 objective lens in a field containing the highest number of clusters. Tumors with

Sarcoidosis is a systemic granulomatous inflammation of unknown etiology, and seems to involve the liver parenchyma in most cases. However, sarcoidosis-associated hepatocellular carcinoma is rare. We report here a case in which a hepatocellular carcinoma occurred within the liver, which was probably involved as a result of systemic sarcoidosis. A 57-year-old Japanese man had been followed up for 2 years because of diabetic nephropathy and sarcoidosis. On admission for pneumonia, imaging studies revealed an unexpected hepatic tumor. Histology revealed a hepatocellular carcinoma accompanied by T-lymphocytic infiltration and marked granulomatous inflammation, which was surrounding some tumor nodules. The background liver parenchyma exhibited a moderate degree of fibrosis with granulomatous inflammation. The patient had no other apparent liver disease such as viral hepatitis, steatohepatitis, or primary biliary cirrhosis. Therefore, in the present case, sarcoidosis may be considered the probable background etiology for hepatocarcinogenesis.

OBJECTIVE To examine glucose-regulated protein 78 (GRP78; a major molecular chaperone at the endoplasmic reticulum, strongly expressed in several tumours) expression in urothelial carcinoma (UC) of the upper urinary tract (UUT) and to evaluate the diagnostic and progressive importance of GRP78 expression in UC-UUT. PATIENTS AND METHODS We investigated GRP78 expression (using immunohistochemistry) in 126 UC-UUTs to assess its relevance to progression. GRP78 overexpression was recognised in 23 (18.3%) of tumour samples. RESULTS There was no association between GRP78 overexpression and clinicopathological findings, except for an association with low grade in invasive tumours. GRP78 overexpression significantly improved the disease-free survival rate in all patients (according to univariate and multivariate analyses), but did not alter the overall survival rate. CONCLUSION The detection of GRP78 overexpression would appear to provide valuable information for the prognosis of UC-UUT.

Lymphohistiocytoid mesothelioma (LHM), reported to be a rare variant of sarcomatoid mesothelioma, is challenging to differentiate from non-Hodgkin's lymphoma due to marked lymphocytic infiltration. To aid accurate recognition of LHM, we examined immunohistochemical, in situ hybridization (ISH) of Epstein-Barr virus RNA (EBER-1) mRNA, fluorescence ISH (FISH) for homozygous deletion of 9p21, and asbestos analysis in four cases (three men and 1 woman). Three patients died, while Case 4 was still alive 19 months after extrapleural pneumonectomy. Histologically, these cases were characterized by heavy lymphocytic infiltration. All neoplastic cells were positive for calretinin, AE1/AE3, and epithelial membrane antigen, but negative for CEA. EBER1 factor was negative. FISH analysis demonstrated homozygous deletion of the 9p21 locus in three of the four cases. In Case 1: (i) autopsy findings showed mesothelioma primarily located in the right parietal pleura, but metastasized into the left lung and abdominal organs; (ii) the histological findings at autopsy indicated sarcomatoid mesothelioma; and (iii) we found asbestos bodies and fibers in extracts from lung tissue (Cases 1 & 4) using digestion with bleaching fluid. LHM, an infrequent variant of sarcomatoid mesothelioma, displayed homozygous deletion of the 9p21 locus (three of four cases), and has a relatively favorable prognosis for the sarcomatoid type.

Although extremely rare, pancreatic SFT does occur. ICC is effective, and indeed essential, for diagnosing such a mesenchymal tumor, especially when there is extensive myxoid change.

Melanoma metastasizing to the lungs is common, but primary pulmonary or pleural melanoma is extremely rare. We present an autopsy case of malignant melanoma of the pleura without primary skin lesion in a 49-year-old man. A mass found in the right chest was diagnosed as spindle cell sarcoma by antemortem fine-needle aspiration cytology. At autopsy, a yellow-white tumor located primarily in the right visceral pleura (diagnosed as an amelanotic melanoma) was found to have invaded into the right lung, right parietal pleura, and right diaphragm, and to have metastasized into the left lung and visceral pleura, thyroid, and left adrenal gland. No primary site was found. The tumor cells were positive for S100 and focally positive for HMB-45, but negative for other markers. Immuno-histochemical examination for S100 and HMB-45 would thus appear to be useful for the diagnosis of an amelanotic melanoma.

Hepatocyte growth factor (HGF) was originally identified as a molecule that could stimulate DNA synthesis in rat and human hepatocytes by autophosphorylation of the proto-oncogene c-met, which is a high-affinity receptor for HGF. Although it was at first considered that HGF could exert biological effects only on specific target cells, it has since been demonstrated that HGF mediates inflammatory responses to tissue injury and also regulates cell growth, cell motility, and morphogenesis in a wide variety of cell types, including cells within the nervous system. In the nervous system, HGF plays a role as a potent neurotrophic and angiogenetic factor. This factor promotes both the survival of neurons and the regeneration of injured nerves, and may also function as target-derived axonal chemoattractants, guiding axons to their target. These observations raised hopes that HGF protein might be useful for the clinical treatment of nervous system disorders. However, administration of HGF as a recombinant protein is still beset by a number of problems, such as a short serum half-life and poor access to the central nervous system by the systemic route because of the presence of the blood-brain barrier. These problems can be major obstacles to the clinical use of this factor in a recombinant protein form, and has highlighted the need to develop innovative therapeutic strategies for more efficient delivery into the nervous system. Gene transfer into the nervous system has enormous therapeutic potential for a wide variety of disorders. It appears to have advantages over the administration of single or multiple bolus doses of a recombinant protein because gene transfer can achieve an optimally high, local concentration within the nervous system. In this article, we demonstrate the efficacy of HGF gene transfer and provide an overview of ideal treatment regimes for various nervous injuries and disorders.

Background: The serum levels of soluble elastin increase in patients with aortic dissection, but its distribution and characteristics are unclear. Methods and Results: The 173 aortic specimens were categorized into 4 groups under microscopy (non-atherosclerotic aorta, n=13; fiber-rich plaque, n=77; lipid-rich plaque, n=66; ruptured plaque, n=17). Soluble elastin was abundant within the intima of both the non-atherosclerotic aorta and fiber-rich plaque, rather than in the media, and was decreased within the intima of lipid-rich and ruptured plaques. Soluble elastin levels decreased with progress of atherosclerosis (6.0 ±0.3 μg/mg protein in non-atherosclerotic aorta; 5.8 ±0.2 μg/mg protein in fiber-rich plaque; 4.9 ±0.2 μg/mg protein in lipid-rich plaque; 2.8 ±0.4 μg/mg protein in ruptured plaque, P

Peripheral nerve injury occasionally causes chronic neuropathic pain with hyperalgesia and allodynia. However, its treatment is difficult. Here, we used a chronic constriction injury (CCI) model in rats to investigate the effects on experimental neuropathic pain of the human hepatocyte growth factor (HGF) gene delivered into the nervous system by retrograde axonal transport following its repeated intramuscular transfer, using liposomes containing the hemagglutinating virus of Japan (HVJ). CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind paw. All these changes were significantly reversed by HGF gene transfer. In the sciatic nerve in HGF-treated rats, the size-frequency distributions for myelinated and unmyelinated axons each showed a rightward shift, the number of myelinated axons5 microm in diameter was significantly increased, and the mean diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs, and of interleukin-6 (IL-6) and activating transcription factor 3 (ATF3) mRNAs, were elevated in the ipsilateral dorsal root ganglia and/or sciatic nerve by CCI, and these levels were decreased by HGF gene transfer. These results may point toward a potential new treatment strategy for chronic neuropathic pain in this model.

The contacts between epithelial cells are maintained mainly by adherens junctions and tight junctions (TJs). However, the role of TJ proteins in cancer is not well understood. We studied the expression of occludin and 4 claudins to assess their importance in the progression of urothelial carcinoma of the upper urinary tract (UC-UUT). In 129 cases, we examined their expression using immunohistochemical analysis and also their relationships to clinicopathologic parameters and clinical outcome. Positive expression of occludin and claudins 1, 3, 4, and 7 were recognized in 117 (90.7%), 113 (87.6%), 95 (73.6%), 127 (98.4%), and 123 (95.3%) of tumor samples, respectively. Claudin-3 expression was significantly associated with stage, grade, and pattern of growth. Claudins 1 and 4 expression was significantly associated with stage. However, neither occludin nor claudin-7 expression was associated with clinicopathologic findings. When tumors with scores below the median for a given protein were classified as the "low expression group," univariate analysis of overall survival revealed that claudins 1 and 3 had a significant effect on overall survival. Detection of claudins 1, 3, and 4 would seem to provide valuable information about the progression of UC-UUT.

Recently, claudin-4 (CL4) immunocytochemistry was reported to be useful for differential diagnosis in effusion cytology. We wondered whether CL4 might be useful for "single-shot" identification of metastatic carcinoma. The purpose of this study was to evaluate the usefulness of CL4 in effusion cytology.In total, 266 cases (169 metastatic carcinomas, eight malignant mesotheliomas, and 89 reactive mesothelial cells) were selected. Immunocytochemical examinations of cell-block sections were performed for CL4, Ber-EP4, and MOC-31. We used an arbitrary 4-tiered scale based on both staining intensity and positive-cell percentage among all target cells, and calculated a staining index score (sum of the above two scores).In a ROC-curve analysis, higher area-under-curve values were found for CL4 than for Ber-EP4 or MOC-31 (0.982, 0.942, and 0.926, respectively).Since CL4 exhibited similar or superior usefulness to Ber-EP4 and MOC-31, it could become the first choice for the above differential diagnosis in effusion cytology. Diagn. Cytopathol. 2016;44:499-504. © 2016 Wiley Periodicals, Inc.

Human intestinal spirochetosis (HIS) is a colorectal bacterial infection, and its clinicopathologic features remain unclear. The aim of this study was to examine its characteristics. We histologically reviewed paraffin-embedded section slides made in 2001, 2006, and 2011 at a single institution in Japan. Cases histologically exhibiting a distinct fringe formation were considered to have HIS. Information was obtained from pathology request forms. We identified 85 HIS cases among 4930 patients (7 cases [0.5%) in 2001, 29 [1.7%] in 2006, and 49 [2.8%] in 2011]. Gastrointestinal symptoms were observed in 7.1% of HIS cases. Human intestinal spirochetosis was more frequent in the right-side large intestine than in the left side. Among 224 samples from HIS cases, conventional (tubular, tubulovillous, and villous) adenomas were found in 148 samples. These adenomas were more frequent in the right side than in the left side, although neither their size nor morphology differed between the sides. Histopathologic evaluation suggested a year-upon-year increasing prevalence of HIS in Japan. A small number exhibited gastrointestinal symptoms. Both histologic sign of HIS and conventional adenomas were more frequent in the right-side large intestine. Therefore, a right-side preference may be a characteristic of HIS.

Background: Telomeres are important for chromosome structure and function, protecting them against degradation. However, few studies have examined telomeres in pulmonary neuroendocrine (NE) tumors. Methods: We investigated deparaffinized sections obtained from 70 primary NE lung tumors [34 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 16 large cell neuroendocrine carcinoma (LCNECs) and 10 small cell lung carcinomas (SCLCs)]. Results: Positive expressions of human telomerase mRNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA were recognized, respectively, in 58% and 74% of TCs, and in 100% and 100% of ACs, LCNECs and SCLCs. Alteration of telomere length was greater in both LCNECs and SCLCs than in TCs. Telomerase activity was detected in LCNECs, but not in TCs. By the reverse-transcriptase polymerase chain reaction (RT-PCR), hTERC mRNA was detected in 100% of LCNECs and TCs examined, while hTERT mRNA was detected in 67% of LCNECs, but not at all in TCs. Conclusions: These results suggest that alterations in telomere length, telomerase activity, and the expression of hTERT mRNA may (i) play roles in pathogenesis in pulmonary neuroendocrine tumors, and (ii) be a useful tool for differential diagnosis between TCs and LCNECs.

No previous study has investigated neutral large amino acid transporter type 1 (LAT1) in normal lung cells, or in atypical adenomatous hyperplasia(s) (AAH) and nonmucinous bronchioloalveolar carcinoma(s) (NMBAC) of the lung. The authors examined: (1) the levels of LAT1 mRNA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 41 normal lung tissues and 34 NMBAC using semiquantitative reverse transcription-polymerase chain reaction; (2) LAT1 mRNA and protein expressions in 35 normal lung tissues, 34 AAH (11 lesions were interpreted as low-grade AAH and 23 as high-grade AAH), and 43 NMBAC using in situ hybridization and immunohistochemistry; and (2) the association of the incidences of LAT1 mRNA and protein expressions with cell proliferation in these lesions. The level of LAT1 mRNA/GAPDH mRNA (1) tended to be higher in NMBAC (12.0+/-8.1) than in normal lung tissues (1.0+/-0.2), and (2) covered a much wider range (from 0 to 276) in NMBAC than in normal lung tissues (from 0 to 5.8), with six NMBAC having values higher than 7.0, while 5.8 was the highest value detected in normal lung tissues. In peripheral normal lung tissues, LAT1 mRNA and protein were detected in bronchial surface epithelial cells and alveolar macrophages (but not in nonciliated bronchiolar epithelial cells, or in alveolar type I or type II cells). In bronchial surface epithelial cells, LAT1 protein appeared to be of a nodular type, which was considered to be a nonfunctional protein pattern. The incidences of positive expressions for LAT1 mRNA and protein were 54.5 and 27.3% in low-grade AAH, 65.2 and 52.2% in high-grade AAH, and 65.1 and 79.1% in NMBAC, respectively. In the case of LAT1 protein expression, significant differences could be shown between total (low-grade plus high-grade) AAH and NMBAC, and between low-grade AAH and NMBAC. Thus, in terms of the incidence of LAT1 protein expression, high-grade AAH appeared intermediate between low-grade AAH and NMBAC. The Ki-67 labeling index (a cell proliferation score) was significantly higher in those AAH and NMBAC that were LTA1-protein-positive than in their LAT1-protein-negative counterparts. In conclusion, LAT1 expression may increase with the upregulation of metabolic activity and cell proliferation in high-grade AAH and NMBAC.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis. Elevated levels of HIF-1alpha, a subunit of HIF-1, are noted in various malignant tumors, but it is unclear whether this is so in esophageal carcinoma. The purpose of this study was to evaluate the implications of HIF-1alpha expression in esophageal squamous cell carcinoma. In 215 patients with esophageal carcinoma, we examined immunoreactivity for HIF-1alpha protein, vascular endothelial growth factor (VEGF) protein and p53 protein. In 38 patients, we examined the expression of HIF-1alpha messenger ribonucleic acid (mRNA) (using the semiquantitative reverse transcriptase-polymerase chain reaction [RT-PCR]). A positive HIF-1alpha protein expression was recognized in 95% of the patients, and was strongly apparent within both the nuclei and/or cytoplasm of tumor cells. The proportion of patients in the 'high score' group for HIF-1alpha protein expression increased significantly with increasing VEGF protein expression. Immunoreactivity for HIF-1alpha protein was found to have a significant effect on disease-free survival rate in our univariate analysis, but no effect on overall survival rate. In RT-PCR, HIF-1alpha mRNA scores correlated significantly with scores for HIF-1alpha protein expression, but not with any clinicopathologic factor or either of the survival rates. The detection of HIF-1alpha protein and mRNA would appear to offer limited information as to progression and prognosis in esophageal carcinoma.

High-altitude hypoxia causes pulmonary hypertension in humans and animals. Endothelin-1 (ET-1) is a novel and long-lasting vasoconstrictor. However, no study has dealt with the effects of a hypobaric hypoxic environment (HHE) on ET-1 activity in the brain. We examined 134 male rats permanently exposed to the equivalent of 5500 m altitude for 1 to 8 weeks. In these HHE rats, the mean pulmonary arterial pressure was significantly raised. The level of ET-1 protein, measured by enzyme immunoassay, increased rapidly in the lungs on exposure to HHE, but decreased in the brain. The level of ET-1 mRNA, measured by semiquantitative RT-PCR, was raised at 1, 4, and 6 weeks' exposure in the lungs and at 4 or more weeks' exposure in 3 of 8 brain regions. By in situ hybridization and immunohistochemistry of brain sections, ET-1 mRNA and protein were detected in the endothelial cells, neurons, and astrocyte-like cells in control rats. In HHE rats, the immunoreactive intensity for ET-1 protein decreased rapidly with time in these cells within the brain, although a few weakly ET-1 protein-positive cells were detected until 8 weeks' exposure to HHE. Only a few weakly ET-1 mRNA-positive endothelial cells were detected in any HHE rats. Although the reactivity for ET-1 mRNA had decreased significantly in neurons and astrocyte-like cells at 1 and 2 weeks' exposure to HHE, it was again strong in both types of cells at 4 weeks' exposure to HHE. These results raise the possibility that during exposure to HHE, ET-1 production in the lung may play a role in the development of pulmonary hypertension, while a decrease in ET-1 production within the brain may help to protect neurons by preventing or limiting the constriction of cerebral microvessels during the hypoxia induced by HHE.