A case of pancreatic PEComa with prominent inflammatory cell infiltration: the inflammatory subtype is a distinct histologic group of PEComa.

BACKGROUND: PEComa is a mesenchymal tumor that can occur in various organs including the uterus and soft tissues. PEComas are composed of perivascular epithelioid cells, and angiomyolipoma (AML), clear cell sugar tumor (CCST), and lymphangiomyomatosis (LAM) are considered lesions of the same lineage as tumors of the PEComa family. Histologically, a common PEComa shows solid or sheet-like proliferation of epithelioid cells. This is accompanied by an increase in the number of dilated blood vessels. Here, we report a case of pancreatic PEComa with marked inflammatory cell infiltration. CASE PRESENTATION: A 74-year-old male patient underwent an appendectomy for acute appendicitis. Postoperative computed tomography and magnetic resonance imaging revealed a 30 × 25 mm non-contrast-enhanced circular lesion in the tail of the pancreas. The imaging findings were consistent with a malignant tumor, and distal pancreatectomy was performed. Histologically, most area of the lesion was infiltrated with inflammatory cells. A few epithelioid cells with large, round nuclei, distinct nucleoli, and eosinophilic granular cytoplasm were observed. Spindle-shaped tumor cells were observed. Delicate and dilated blood vessels were observed around the tumor cells. Immunohistochemically, the atypical cells were positive for αSMA, Melan A, HMB-45, and TFE3. The cytological characteristics of the tumor cells and the results of immunohistochemical staining led to a diagnosis of pancreatic PEComa. CONCLUSIONS: A histological variant known as the inflammatory subtype has been defined for hepatic AML. A small number of tumor cells present with marked inflammatory cell infiltration, accounting for more than half of the lesions, and an inflammatory myofibroblastic tumor-like appearance. To our knowledge, this is the first report of pancreatic PEComa with severe inflammation. PEComa is also a generic term for tumors derived from perivascular epithelioid cells, such as AML, CCST, and LAM. Thus, this case is considered an inflammatory subtype of PEComa. It has a distinctive morphology that is not typical of PEComa. This histological phenotype should be widely recognized.

Collision of Epstein-Barr virus-positive and -negative gastric cancer, diagnosed by molecular analysis: a case report.

BACKGROUND: Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) is defined by the proliferation of GC cells with EBV infection. The co-existence of EBV-positive and -negative components in a single GC is rare. We report a case of GC with the co-existence of EBV-positive and EBV-negative components, in which we performed-for the first time-various molecular analyses to elucidate their histogenesis. CASE PRESENTATION: An 81-year-old man was diagnosed with GC based on the results of endoscopy and a pathological examination of the biopsy specimen. Systemic chemotherapy was performed, since lymph node and lung metastases were diagnosed based on computed tomography. Total gastrectomy and lymph node dissection were performed after chemotherapy, after confirming that the size of the metastatic lymph nodes had decreased and that the lung metastasis had disappeared. Grossly, a type 3 tumor was located in the middle posterior part of the stomach body. At the cut section, the tumor consisted of a white and solid part on the anal side of the tumor and a flat and elevated part on the oral side. Histologically, the former part consisted of GC with lymphoid stroma and the latter part was composed of poorly differentiated adenocarcinoma without prominent lymphocytic infiltration. The two histopathological components were clearly separated from each other. On EBV-encoded small RNA (EBER)-in situ hybridization (ISH), the part with the lymphoid stroma component was positive, while the other part was negative. Immunohistochemistry revealed that both components showed the overexpression of p53. Sequencing of TP53 using DNA extracted from the two components was conducted, and revealed different patterns. Targeted next generation sequencing revealed MYC amplification in the EBV-positive component of the tumor and HER2 amplification in the EBV-negative part. Immunohistochemistry revealed that the EBV-positive part was C-MYC( +)/HER2(-) and the EBV-negative part was C-MYC(-)/HER2( +). Correspondingly, chromogenic ISH and dual-color ISH showed amplification of C-MYC and no amplification of HER2 in the EBV-positive part, and no amplification of C-MYC and amplification of HER2 in the EBV-negative part. CONCLUSION: We presented a case of collision of two different GCs composed of EBER-ISH ( +)/C-MYC ( +) and EBER-ISH (-)/HER2 ( +) cells.

Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

Clinicopathological and molecular analyses of linearly expanded epithelial cells with ß-catenin alterations, "ß-catenin signature", in the normal fallopian tube.

AIMS: Recent advances in next-generation sequencing have made it clear that clonal expansion of cells harbouring driver gene mutations occurs in physiologically normal epithelium. Molecular analysis of tubal epithelium has been almost exclusively confined to the TP53 pathway, which is involved in serous carcinogenesis. Other oncogenic events have not been explored in detail. Here, we report the linear expansion of fallopian tubal epithelial cells exhibiting an altered ß-catenin profile (ß-catenin signature). Through molecular analyses, we determined the incidence and clinicopathological significance of ß-catenin signatures. METHODS AND RESULTS: We evaluated 64 specimens of surgically removed bilateral fallopian tubes. Thirty-three ß-catenin signatures were identified in 13 cases (20.3%); these patients were significantly younger than those without ß-catenin signatures (median ages of 44 and 57 years, respectively, P = 0.0317). No correlation between ß-catenin signature and any clinical factor was observed. CTNNB1 mutations were detected in three of eight ß-catenin signatures when tissues were microdissected and subjected to Sanger sequencing in two representative cases. CONCLUSIONS: This is the first report of the CTNNB1 mutation in clusters of morphologically bland tubal epithelial cells. The results of this study indicate that ß-catenin signatures are common, and they may be a part of diverse molecular alterations occurring in normal tubal epithelium.

Fetal gut-like differentiation in gallbladder cancer.

Adenocarcinomas showing fetal gut-like (enteroblastic) differentiation can arise in a variety of organs and are frequently accompanied by an elevated serum α-fetoprotein (AFP) level. However, no study has investigated fetal gut-like differentiation in gallbladder cancer in detail. Herein, we performed morphological and immunohistochemical analyses of fetal gut-like differentiation in 49 consecutive gallbladder cancer cases. The expression of Sal-like protein 4 (SALL4), an embryonic stem cell marker reported to represent fetal gut-like differentiation, as well as other oncofetal proteins, including glypican-3 (GPC3) and AFP, was assessed. We found 1 case of fetal gut-like adenocarcinoma that coexisted with conventional-type adenocarcinoma. The fetal gut-like adenocarcinoma component revealed diffuse immunoreactivity for SALL4 and partial positivity for AFP, whereas the conventional-type adenocarcinoma component was negative. We also found 2 poorly differentiated adenocarcinomas with hepatoid morphology and 1 clear cell carcinoma, none of which showed SALL4 positivity. In other conventional-type adenocarcinomas, focal immunoreactivity for SALL4 and GPC3 was occasionally observed. The overall positivity rates for SALL4 and GPC3 were 12.2% (6/49) and 16.3% (8/49), respectively. SALL4 and GPC3 expression was not associated with clinicopathological factors, including T category, lymphovascular invasion, and lymph node metastases. In conclusion, fetal gut-like adenocarcinoma was found in 2% of our gallbladder cancer series. We conclude that fetal gut-like adenocarcinoma is a distinct histological subtype of gallbladder cancer, characterized by SALL4 expression.

Telmisartan increases localization of glucose transporter 4 to the plasma membrane and increases glucose uptake via peroxisome proliferator-activated receptor γ in 3T3-L1 adipocytes.

Angiotensin II is a peptide hormone with strong vasoconstrictive action, and recent reports have shown that Angiotensin II receptor type 1 antagonists (angiotensin II receptor blockers) also improve glucose metabolism. The angiotensin II receptor blocker telmisartan acts as an agonistic ligand of the peroxisome proliferator-activated receptor gamma (PPARγ). In this study, we investigated the effects of telmisartan on glucose uptake and insulin sensitivity in 3T3-L1 adipocytes and compared it with the action of other angiotensin II receptor blockers. Telmisartan treatment dose-dependently increased (from 1 µM) protein expression of PPARγ-regulated molecules such as fatty acid binding protein 4 (FABP4), insulin receptor, and glucose transporter 4 (GLUT4). Telmisartan increased glucose uptake both with and without insulin stimulation in 3T3-L1 adipocytes. Telmisartan increased the up-regulation of phosphorylated insulin receptor, insulin receptor substrate-1 (IRS-1) and Akt by insulin, suggesting that telmisartan increases insulin sensitivity. Furthermore, in the absence of insulin, telmisartan, but not candesartan, increased GLUT4 levels at the plasma membrane. These effects by 10 µM telmisartan were similar potency to those of 1 µM troglitazone, an activator of PPARγ. In addition, up-regulation of glucose uptake by telmisartan was inhibited by a PPARγ antagonist, T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide). These results indicate that telmisartan acts via PPARγ activation in adipose tissue and may be an effective therapy for the metabolic syndrome.

Reactive oxygen species induced by diamide inhibit insulin-induced ATP-sensitive potassium channel activation in cultured vascular smooth muscle cells.

Both insulin resistance and reactive oxygen species (ROS) have been reported to play essential pathophysiological roles in cardiovascular diseases. However, the mechanistic link between ROS and insulin resistance in the vasculature remains unclear. Recently we have shown that insulin causes KATP channel activation mediated by PI3K in cultured vascular smooth muscle cells (VSMCs). KATP channel in VSMCs is critical in the regulation of vascular tonus. Here we examined the effects of ROS induced by a thol-oxidizing agent, diamide, on the insulin signalling pathway and KATP channel activities in cultured VSMCs (A10 cells). Diamide (100 microM) increased intercellular ROS and extracellular signal-regulated kinases (ERK) activity. Treatment with 100 M diamide suppressed significantly insulin-induced IRS and Akt phosphorylation. In addition to IRS and Akt, diamide inhibited insulin receptor auto-phosphorylation. Patch-clamp study showed that diamide suppressed insulin-induced but did not pinacidil-induced KATP channel activities in A10 cells. From these data, we conclude that ROS inhibit critical insulin signal transduction components including IRS and Akt, and these effects cause down-regulation of insulin's action in the vasculature including KATP channel activation. This study may contribute to our understanding of mechanisms of insulin resistance-associated cardiovascular disease.

Insulin activates ATP-sensitive potassium channels via phosphatidylinositol 3-kinase in cultured vascular smooth muscle cells.

The effects of insulin on the vasculature are significant because insulin resistance is associated with hypertension. To increase the understanding of the effects of insulin on the vasculature, we analyzed changes in potassium ion transport in cultured vascular smooth muscle cells (VSMCs). Using the potential-sensitive fluorescence dye bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)], we found that insulin induced membrane hyperpolarization after 2 min in A10 cells. Insulin-induced hyperpolarization was suppressed by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. Using a cell-attached patch clamp experiment, the K(ATP) channel was activated by insulin in both A10 cells and isolated VSMCs from rat aortas, indicating that insulin causes membrane hyperpolarization via K(ATP) channel activation. These effects were not dependent on intracellular ATP concentration, but wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, significantly suppressed insulin-induced K(ATP) channel activation. In addition, insulin enhanced phosphorylation of insulin receptor, insulin receptor substrate (IRS)-1 and protein kinase B (Akt) after 2 min. These data suggest that K(ATP) channel activation by insulin is mediated by PI3-K. Furthermore, using a nitric oxide synthase (NOS) inhibitor, we found that NOS might play an important role downstream of PI3-K in insulin-induced K(ATP) channel activation. This study may contribute to our understanding of mechanisms of insulin resistance-associated hypertension.