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Neuropathology ANNUAL MEETING ABSTRACTS 413A PIK3CA in HCC is a novel finding and further investigations may determine if this found. The MDM2 SNP-309 genotypes of HCC were not statistically different from represents feedback inactivation of the mTOR pathway. those of 100 controls. MDM2 SNP-309 Genotypes in HCC and Controls HCC (n = 69) Control (n = 100) G/G 7 (10%) 12 (12%) T/G 30 (43.5%) 40 (40%) T/T 32 (46.4%) 48 (48%) p = 0.981 No correlation was observed between MDM2 SNP-309 genotype, MDM4 and p53 expression level and median overall survival time. Conclusions: Aberrant activation of MDM4 is frequently present in HCC and could represent a common mechanism by which wild-type p53 is inactivated. It is unlikely that MDM2 SNP-309 or over-expression of MDM2 contribute to p53 inactivation. We are currently evaluating the potential mechanism of MDM4 over-expression and the correlation with p53 mutation status. Neuropathology 1722 Altered Telomeres with Loss of ATRX Protein Are Frequently Seen in High-Grade Pediatric Gliomas M Abedalthagafi, J Phillips, D Ellison, A Judkins, S Mueller, R Marshall, D Haas- Kogan, A Perry. University of California San Francisco, San Francisco, CA; St. Jude Children’s Research Hospital, Memphis, TN; University of Pennsylvania Health System, Philadelphia, PA. 1720 Aberrant von Willebrand Factor (vWF) Expression of Sinusoidal Background: Loss of function of alpha thalassemia/mental retardation syndrome Endothelial Cells in Nodular Regenerative Hyperplasia and Obliterative X-linked (ATRX) protein leads to a phenotype called alternative lengthening of Portal Venopathy telomeres (ALT). Mutations that inactivate these genes are common in human pancreatic X Zhang, TD Schiano, SN Thung, SC Ward, MI Fiel. Yale University School of Medicine, neuroendocrine tumors (PanNETs) and CNS tumors. New Haven, CT; Mount Sinai Medical Center, New York, NY. Design: We examined 60 cases of high-grade pediatric gliomas of various histological Background: Nodular regenerative hyperplasia (NRH) and obliterative portal types and looked for loss of ATRX with immunocytochemistry and the presence of venopathy (OPV) are under-recognized diseases of uncertain etiology that result in ALT with telomere-specific fluorescence in situ hybridization. noncirrhotic portal hypertension (NCPH). The diagnosis can be easily missed on Results: Using a large cohort from multiple institution of high-grade pediatric gliomas needle liver biopsy. CD34 and vWF are commonly used endothelial markers. vWF is (n = 60) we found that 33.33% of tumors were ALT positive (20/60) (Figure 1), and released by activated endothelial cells and plays a crucial role in primary hemostasis 75% of tumors with undetectable ATRX were positive for ALT (15/20) (Figure 2). and in the development of thrombotic vascular obliteration. Liver sinusoidal endothelial cells (LSEC) are unique in that the expression of CD34 and vWF are confined only to periportal areas in the normal liver. We sought to investigate the potential utility of these two immunomarkers in helping make the diagnosis of NRH and OPV. Additionally, the immunoexpression pattern may further elucidate the pathogenesis of these conditions. Design: Re-review of the histology of liver wedge and needle biopsies of clinically proven NCPH cases was undertaken. NRH is defined as small hyperplastic nodules centered around portal tracts compressing adjacent atrophic hepatocytes and sinusoids whereas OPV, although having heterogeneous histology, commonly demonstrates different degrees of phlebosclerosis and dense portal fibrosis. Cases with combined OPV and NRH on biopsy were also noted. Immunohistochemical staining for CD34 and vWF (DAKO, Carpinteria, CA) was performed using standard methods. Results: There were 15 NRH, 25 OPV and 5 normal liver biopsies (acting as controls). Among the 25 OPV, 20 had concurrent features of NRH (80%). CD34 (+) staining was mainly confined to small vessels in the portal tracts as well as LSECs in periportal areas in both NRH and OPV, similar to that in the normal control biopsies. Unlike CD34, expression of vWF in LSECs was (+) along the dilated sinusoids of NRH, and in a patchy or geographic pattern, particularly prominent in the perivenular areas of OPV as opposed to vWF expression being confined to periportal areas in the controls. Conclusions: NRH and OPV are commonly seen together in the same liver biopsy. The aberrant expression of vWF in NRH and OPV suggest that LSEC activation is involved in their pathogenesis and that NRH and OPV may share a common pathway of vascular injury. The aberrant expression pattern of vWF may also aid in the histologic diagnosis and recognition of NRH and OPV on liver biopsy. 1721 The p53 Negative Regulator, MDM4 but Not MDM2, Is Frequently Activated in Hepatocellular Carcinoma X Zhou, M Bloomston, LA Shirley, A Lozanski, G Lozanski, WL Frankel. Ohio State University, Columbus, OH. Background: The p53 tumor suppressor pathway is frequently inactivated in human cancers including hepatocellular carcinoma (HCC). MDM2 and MDM4 are the primary negative regulators of p53. Amplification or over-expression of MDM2 and MDM4 abolish the p53 mediated response by inactivating the wild-type p53 protein. A functional single nucleotide polymorphism of the MDM2 (SNP-309 T/G) enhances the Sp1 binding to MDM2 promoter and MDM2 expression resulting in attenuation of p53 and has been associated with the development and prognosis of a number of tumors. We hypothesized that over-expression of MDM2 and MDM4 may be the common mechanism of p53 inactivation in HCC and thus a potential therapeutic target. Design: Tissue microarrays of HCC were constructed and immunohistochemically stained for MDM2, MDM4 and p53. Expression intensity was scored as 0 (absent), 1+ (modest) or 2+ (high). Genotyping of MDM2 SNP-309 was performed on genomic DNA extracted from tumor by PCR amplification flanking the corresponding promoter region followed by temperature gradient capillary electrophoresis and direct sequencing. We evaluated the association between MDM2 SNP-309 and the risk of HCC by comparing the genotype frequency with that of controls. We also investigated the relationships Conclusions: Further understanding of the role of ATRX/DAXX and histone H3.3 in between MDM2 SNP-309 genotype, MDM2, MDM4 and p53 expression and median GBM pathogenesis may lead to more accurate prognosis and stratification of patients overall survival time. to the most appropriate therapies. ALT/ATRX may serve as a potential screening and Results: MDM4 expression was detected in 42 of 93 HCC (45%; 1+ in 33, 2+ in 9), prognostic marker in patients with pediatric gliomas. Our results show that telomere- p53 was detected in 6 (6%; 1+ in 4, 2+ in 2), and no MDM2 immunoreactivity was 414A ANNUAL MEETING ABSTRACTS specific FISH and ATRX staining are reliable assays of choice for formalin-fixed tissue. in a small number of cases, we wished to test the hypothesis that SST2A could prove Other genetic markers in addition to ATRX may help classify patients, leading to more to be a highy sensitive and specific marker of meningioma. accurate prognosis and more successful treatment strategies. In addition, targeting Design: 27 cases of meningiomas and 21 cases of schannomas, hemangiopericytoma/ molecules that play a role in chromosome remodeling and telomere stability, including solitary fibrous tumors, or gliomas were obtained from the files of PhenoPath telomerase and ALT-related proteins, may be a strategy for developing new treatments Laboratories and Consultoria em Pathologia. Deparaffinized, formalin fixed tissues were for these highly aggressive pediatric cancers. Finally, our data highlight the distinction incubated with antibodies to SST2A [rabbit monoclonal antibody UMB1 (Epitomics, between adult and pediatric gliomas. Burlingame, CA) with localization by the Quanto polymer based detection system (ThermoFisher, Waltham, MA)]. A semiquantitative scoring system was employed based 1723 Canonical TGF-Beta Pathway Activity Is a Predictor of SHH- upon the fraction of tumor cells showing positivity (low, <25% of tumor cells positive; Driven Medulloblastoma Survival intermediate, 26-75% of tumor cells positive; high, >75% of tumor cells positive). Results: 27/27 (100%) of meningiomas were positive for expression of SST2A, virtually D Aref, CJ Moffatt, S Agnihotri, A Dubuc, MD Taylor, A Perry, C Eberhardt, S Croul. all of them strong and uniform (nearly 100% of tumor cells positive). In contrast, 2/21 University of Toronto, Toronto, ON, Canada; Hospital for Sick Children, Toronto, non-meningiomas (both hemangiopericytoma/solitary fibrous tumors) demonstrated ON, Canada; UCSF, San Francisco, CA; Johns Hopkins University, Baltimore, MD. positivity, albeit focal. Thus, the sensitivity of SST2A for meningiomas was 100% Background: Medulloblastoma, an embryonal neuroepithelial tumour arising in with 90% specificity, based upon the limited tissues studied. the cerebellum, is the most common malignant brain tumor of childhood. Although Conclusions: SST2A is one of two isoforms of the somatostatin 2 receptor, which current treatment regimens have significantly improved survival over the past decades, in turn is one of five subtypes of somatostatin receptors. SST2A has been previously recurrent and/or metastatic MB still spell poor prognosis for patients. Aggressiveness demonstrated to localize to neuroendocrine tumors, and has also been used as an is marked by increased growth and decreased responsiveness to available therapies. immunohistochemical
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