YWHAE Rearrangement in a Purely Conventional Low-grade Endometrial Stromal Sarcoma that Transformed Over Time to High-grade Sarcoma: Importance of Molecular Testing.

Low and high-grade endometrial stromal sarcomas (ESS) can be distinguished on a morphologic basis. Low-grade ESS is composed of oval cells that resemble normal proliferative-phase endometrial stroma, while the well-known high-grade ESS is composed of round cells growing in nests separated by delicate sinusoidal vasculature. Recurrent JAZF1 rearrangements have been reported to be most frequent in low-grade stromal sarcomas (up to 60%), while YWHAE rearrangements are characteristic of high-grade ESS. Herein, we report a case of a 45-yr-old woman with stage IA typical low-grade ESS who developed multiple abdominopelvic recurrences and lung metastases 15 mo after her primary tumor was resected. The unusual morphology (without high-grade areas) as well as the aggressive behavior of the tumor prompted molecular testing which showed YWHAE rearrangement in her abdominopelvic recurrence and her primary tumor. Five years after her primary tumor was resected, she developed scalp metastases with a typical morphology of a high-grade ESS associated with t(10;17) and died of her disease. Our case highlights the potential value of molecular testing in all low-grade ESS at time of initial diagnosis to stratify patients at higher risk for developing high-grade ESS with the goal of offering closer follow-up for early detection and treatment if transformation occurs.

TRPM8 activation attenuates inflammatory responses in mouse models of colitis.

Transient Receptor Potential Melastatin-8 (TRPM8), a recently identified member of the transient receptor potential (TRP) family of ion channels, is activated by mild cooling and by chemical compounds such as the supercooling agent, icilin. Since cooling, possibly involving TRPM8 stimulation, diminishes injury-induced peripheral inflammation, we hypothesized that TRPM8 activation may also attenuate systemic inflammation. We thus studied the involvement of TRPM8 in regulating colonic inflammation using two mouse models of chemically induced colitis. TRPM8 expression, localized immunohistochemically in transgenic TRPM8(GFP) mouse colon, was up-regulated in both human- and murine-inflamed colon samples, as measured by real-time PCR. Wild-type mice (but not TRPM8-nulls) treated systemically with the TRPM8 agonist, icilin showed an attenuation of chemically induced colitis, as reflected by a decrease in macroscopic and microscopic damage scores, bowel thickness, and myeloperoxidase activity compared with untreated animals. Furthermore, icilin treatment reduced the 2,4,6-trinitrobenzenesulfonic acid-induced increase in levels of inflammatory cytokines and chemokines in the colon. In comparison with wild-type mice, Dextran Sodium Sulfate (DSS)-treated TRPM8 knockout mice showed elevated colonic levels of the inflammatory neuropeptide calcitonin-gene-related peptide, although inflammatory indices were equivalent for both groups. Further, TRPM8 activation by icilin blocked capsaicin-triggered calcitonin-gene-related peptide release from colon tissue ex vivo and blocked capsaicin-triggered calcium signaling in Transient Receptor Potential Vaniloid-1 (TRPV1) and TRPM8 transfected HEK cells. Our data document an anti-inflammatory role for TRPM8 activation, in part due to an inhibiton of neuropeptide release, pointing to a novel therapeutic target for colitis and other inflammatory diseases.

Upper gastrointestinal bleed as the initial presentation of seminoma involving the duodenum in an elderly patient with 9 year follow up: A case report and literature review.

Germ cell tumors are the most common malignancies in males between 20 and 40 years. However, primary extragonadal germ cell tumors are rare and account for 2%-5% of all germ cell neoplasms in adults. Extragonadal germ cell tumors are characterized by their midline locations including pineal and suprasellar regions, mediastinum, retroperitoneum and sacrococcyx. These tumors have also been reported in rare locations such as prostate, bladder, vagina, liver and scalp. Extragonadal germ cell tumors can be primary but may also represent metastases from primary gonadal germ cell tumors. In this report we describe a case of a duodenal seminoma in a 66-year-old male with no history of testicular tumors, who presented with upper gastrointestinal bleed as the initial manifestation. He was effectively treated with chemotherapy and continues to progress well clinically, with no episodes of recurrence.

Forty year follow-up of three patients with complete absence of apolipoprotein B-containing lipoproteins.

Complete deficiency of apolipoprotein (apo) B-containing lipoproteins can result from both abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HoHBL), caused by bi-allelic loss-of-function variants in the MTTP and APOB genes encoding microsomal triglyceride transfer protein and apolipoprotein (apo) B, respectively. Both conditions are associated with failure to assemble and secrete apo B-containing lipoproteins from intestine and liver, resulting in absence of chylomicrons, very low-density lipoproteins and remnants, and low-density lipoproteins. Because absorption and transport of fat soluble vitamins requires intact production of apo B-containing lipoproteins, untreated patients develop fat soluble vitamin deficiencies, with associated clinical features including atypical retinitis pigmentosa, osteopenia, neuromyopathy and coagulopathy. Other features include acanthocytosis on the peripheral blood film, fat malabsorption and hepatosteatosis. We describe two patients with ABL and one with HoHBL who have each been on high dose oral fat soluble vitamin replacement under the care of the same physician for more than four decades. Each patient has remained clinically stable. A recent liver biopsy from an ABL patient showed mild macrovesicular steatosis, patchy microvesicular steatosis and mild fibrosis. These observations add to our understanding of the long term trajectory of ABL and HoHBL, and emphasize the importance of compliance to treatment and follow up.

Involvement of cytosolic phospholipase A2 alpha signalling pathway in spontaneous and transforming growth factor-beta-induced activation of rat hepatic stellate cells.

BACKGROUND: Hepatic stellate cells (HSCs) are extracellular matrix-producing cells that play a pivotal role in liver fibrogenesis. During liver injury and when cells are placed in vitro, HSCs undergo phenotypic transition from quiescent retinoid-storing cells to activated retinoid-deficient myofibroblast-like cells. Although several mediators including reactive oxygen species, platelet derived growth factor, transforming growth factor-beta (TGF-ß) and tumour necrosis factor-alpha (TNF-α) were implicated in HSC activation, the cellular signalling pathways that regulate this process remain incompletely defined. AIMS: The objectives of this study were to evaluate the role of cytosolic phospholipase A(2) alpha (cPLA(2)α) and peroxisome proliferator-activated receptor-beta/delta (PPAR-ß/δ) in HSC activation. METHODS: Rat HSCs were isolated, purified, cultured and stimulated with TGF-ß1 in the presence or absence of the selective cPLA(2)α inhibitor, arachidonyltrifluoromethyl ketone (AACOCF(3)). The activation status of HSC was evaluated by immunofluorescent staining of alpha-smooth muscle actin (α-SMA) and by measuring the expression of cPLA(2)α, cyclooxygenase 2 (COX-2) and PPAR-ß/δ using western blot analysis. RESULTS: Rapid and significant increase in cPLA(2)α expression was observed during activation of HSCs. These events preceded the elevation of PPAR-ß/δ and the expression of α-SMA. Elevated expression of cPLA(2)α, but not COX-2, was also observed during TGF-ß-induced HSC activation. The TGF-ß-induced α-SMA expression was blocked by AACOCF(3). Furthermore, transfection of a cPLA(2)α expression vector enhanced the transcription activity of PPAR-ß/δ and the expression of α-SMA in HSCs. CONCLUSION: cPLA(2)α-mediated induction of PPAR-ß/δ is a novel intracellular signalling pathway in spontaneous and TGF-ß induced activation of HSCs and could be a potential therapeutic target for the treatment of liver fibrosis.

Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease.

The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial-mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-beta (TGFbeta) or TGFbeta-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial-mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (alpha-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFbeta and S100A4. Stimulation of cultured cells with TGFbeta induced the expression of pSmad2/3, S100A4 and alpha-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFbeta RI), low levels of TGFbeta mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFbeta mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the 'ductular reaction' expressed both epithelial and mesenchymal markers together with high levels of TGFbeta mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFbeta, possibly presented by infiltrating T cells.

The diffuse stellate cell system.

Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. Morphologically similar cells have been found at extrahepatic sites such as pancreas, kidney and colon. The true phenotypic relationship between these cells has not been fully established. We carried out immunohistochemical staining in normal tissues from liver, kidney, colon, pancreas, lung and heart, obtained from a range of species. Immunoreactivity to antibodies directed to synemin, glial fibrillary acidic protein (GFAP), nestin, neurofilament-L, beta-tubulin, protein gene product 9.5 (PGP9.5), S100, desmin, alpha-smooth muscle actin (alpha-SMA) and vimentin was examined. Synemin was identified in HSCs, pancreatic stellate cells, mesangial cells and in peribronchiolar stellate-shaped fibroblasts. GFAP positivity was detected in HSCs and peribronchiolar stellate-shaped fibroblasts. Desmin immunoreactivity was detected in HSCs, pancreatic stellate cells, mesangial cells, periglomerular and peritubular fibroblasts, subepithelial fibroblasts, as well as in peribronchiolar stellate-shaped fibroblasts. Vimentin expression was evident in HSCs, periductal fibroblasts, pancreatic stellate cells, fibroblasts within the fibroconnective tissue capsule, mesangial cells, subepithelial fibroblasts and the interstitial cells of Cajal, as well as in peribronchiolar fibroblasts. Mesangial cells and peritubular fibroblasts showed nestin immunoreactivity. Our data indicates that mesenchymal cells at extrahepatic sites express many of the neural and muscle-associated proteins seen in HSCs; there are however species differences in the expression pattern of these proteins. The findings support the concept of a diffuse stellate cell system in mammals.

Cytological, molecular, and clinical features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features versus invasive forms of follicular variant of papillary thyroid carcinoma.

BACKGROUND: The noninvasive follicular variant of papillary thyroid carcinoma (PTC) has an indolent clinical behavior in comparison with other PTCs, including the invasive follicular variant of papillary thyroid carcinoma (IFVPTC). Recently, the term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced to emphasize the low biological potential of these tumors. This study compares clinical, cytological, and molecular features of NIFTP and IFVPTC. METHODS: The study consisted of 97 thyroid fine-needle aspiration biopsy (FNAB) cases with corresponding surgical pathology from the pathology archives of the Massachusetts General Hospital. The collected patient data included the following: age, sex, type of surgery, tumor size, and prior cytological diagnosis with The Bethesda System for Reporting Thyroid Cytopathology. A molecular analysis using anchored multiplex polymerase chain reaction was performed for all cases. Each case was reviewed and subclassified histologically as NIFTP or IFVPTC. Cytology slides were scored semiquantitatively for nuclear atypia. The statistical analysis was performed with the nonparametric Mann-Whitney test. RESULTS: The 97-case cohort consisted of 50 NIFTP cases and 47 IFVPTC cases, including 18 encapsulated IFVPTC cases and 29 nonencapsulated IFVPTC cases. Differences in the type of surgery (P = .0399), molecular features (P = .0141), cytological classification (P = .0266), and nuclear scores (P = .0141) between NIFTP and IFVPTC were observed. There was overlap in the cytological classification of NIFTP and IFVPTC; however, NIFTP was more often classified as atypia of undetermined significance/follicular lesion of undetermined significance or follicular neoplasm/suspicious for follicular neoplasm in comparison with both subsets of IFVPTC. NIFTP was primarily associated with mutations in RAS, whereas an equal number of IFVPTC cases were associated with BRAFV600E or with RAS mutations. CONCLUSIONS: Despite differences in the cytological classification and molecular profiles between NIFTP and IFVPTC, the degree of overlap makes it unlikely that most cases of NIFTP and IFVPTC can be accurately distinguished with FNAB. Cancer Cytopathol 2017;125:323-331. © 2017 American Cancer Society.

ERG expression in prostate cancer: biological relevance and clinical implication.

INTRODUCTION: Screening for increased levels of prostate-specific antigen (PSA) has allowed early detection of a large majority of prostate cancer (PCa) cases. However, the relative lack of specificity of PSA has resulted in significant over-diagnosis and unnecessary treatment for indolent tumors. The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes, particularly ERG, is the most widespread genetic alteration in prostate cancer, and data suggest that it is more specific for neoplastic prostate disease and may be of added prognostic value and point toward molecular subtype of PCa. METHODS: In this review, retrospective studies and clinical trials were analyzed to highlight the recent advances in our understanding of the cellular consequence of ERG rearrangement, describe its interactions with other genetic and molecular pathways, and discuss its potential diagnostic and prognostic value. CONCLUSION: ERG over-expression has an emerging role in the diagnosis of PCa pathology, although there is still debate about its prognostic value. Elucidation of the mechanisms of ERG gene rearrangements and expression promises novel therapeutic and diagnostic avenues for prostate cancer.

Malignant perivascular epithelioid cell tumor of the gallbladder: a case report and review of literature.

Perivascular epithelioid cell tumors are rare mesenchymal neoplasms composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell tumor family includes angiomyolipoma, clear cell sugar tumor of the lung, lymphangioleiomyomatosis, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and rare clear cell tumors of other anatomic sites. Perivascular epithelioid cell tumors have been reported previously in various sites, but to our knowledge not in the gallbladder. We report here, for the first time, a malignant perivascular epithelioid cell tumor arising in the gallbladder.

Lichen planus is an uncommon cause of nonspecific proximal esophageal inflammation.

BACKGROUND/AIMS: Esophageal lichen planus (LP) has been described as a cause of nonspecific esophagitis that may cause dysphagia, but its incidence is unknown. We aimed to estimate the incidence of esophageal LP in a defined geographic region and describe the clinical characteristics of affected patients. METHODS: A histopathology database for a population of 1 million people was searched for all esophageal mucosal biopsy results over an 8-year period. Cases showing inflammation or abnormalities without a diagnosis after three or more biopsies were reviewed for findings of LP. RESULTS: Of 13,589 esophageal biopsies, only one received a diagnosis of LP. Seven patients (four male; mean age, 59 years; range, 39 to 76 years) were identified as having chronic dysphagia and nonspecific proximal esophagitis for which no diagnosis could be made. All patients had proximal inflammation, and six of seven had full-thickness lymphocytic infiltration. Elongation of the lamina propria papillae was noted in all patients, whereas six patients had parakeratosis and ballooning. Only one patient had findings potentially consistent with, but not sufficient for, a diagnosis of esophageal LP. CONCLUSIONS: Esophageal LP appears to be extremely uncommon in this North American population, and esophageal biopsy alone is likely not sufficient to establish a diagnosis of LP.

A case report of an extremely rare and aggressive tumor: primary malignant pericardial mesothelioma.

Primary pericardial malignant mesothelioma (PMPM) is extremely rare with an incidence less than 0.0022%. It comprises 0.7% of all mesothelioma cases. To date, approximately 350 cases of pericardial mesothelioma have been reported in the literature. Its typical presentation is insidious, with nonspecific signs and symptoms, and usually results in constrictive pericarditis, cardiac tamponade and congestive heart failure either by a serous effusion or by direct tumorous constriction of the heart. With the exception of several case reports, the outcome is uniformly fatal, and patients typically die within six months of diagnosis. Here we report a 72-year-old Cauca -sian male with persistent pericardial and pleural effusion. He was diagnosed with PMPM after pericardectomy. He had only one cycle of chemotherapy with cisplatin and pemetrexed. He developed acute kidney injury as result of chemotherapy. He died 1 month after diagnosis and 6 months after the first symptoms.

ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo.

ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.