Tumor necrosis factor (TNF) mediates a variety of biological activities including cell proliferation, differentiation and programmed cell death. The specific response to TNF depends upon cell type and reflects the presence of specific regulatory proteins that participate in the TNF response pathway. TNF signal transduction is mediated by TRAF2 which binds the TNF Receptor2 (TNFR2) and activates NFkappaB. We previously identified a gene Pw1, which encodes a large zinc-finger containing protein. We have determined that Pw1 is identical to Peg3, a paternally expressed gene of unknown function (and will therefore be referred to as Peg3 throughout this text). We report here that Peg3 associates specifically with TRAF2 but not with other TRAF family members. Peg3 expression activates NFkappaB via IkappaB-NFkappaB dissociation and acts synergistically with TRAF2. Transfection of a truncated Peg3 containing the TRAF2 interaction site, abolishes NFkappaB activation by TRAF2 and/or TNF. We conclude that Peg3 is a regulator of the TNF response. These data reveal the involvement of an imprinted gene in this pathway.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) provides a standardized reporting system for salivary gland fine-needle aspiration (SGFNA). We review the clinical utility of the MSRSGC at a tertiary care cancer center by assessing the rates of malignancy (ROM) among different categories.Methods: A retrospective search was performed to retrieve all SGFNA cases performed at our institution between 1/1/07 and 12/31/18. The initial primary diagnoses were recorded and cases were then assigned to appropriate MSRSGC categories. ROM was then calculated for all categories.Results: A total of 976 cases were identified, and 373 with follow-up. The ROM was 19.7% (192/976) for all-comers and 51.3% (192/374) among cases with follow-up.Using MSRSGC, SGFNA showed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 65.6%, 87.4%, 100%, and 72.6%, respectively. ROM for MSRSGC categories I, II, III, IVa, IVb, V, and VI were 20.7%, 30.0%, 45.8%, 3.3%, 50.7%, 100%, and 100%, respectively. Utilizing MSRSGC resulted in a nondiagnostic rate of 14.4%. The nondiagnostic rate was lower when the procedure was performed by pathologists vs nonpathologists (12.9% vs 15.8%) but was comparable when rapid on site evaluation (ROSE) was performed (12.9% vs 11.6%).Conclusion: In our patient population, MSRSGC resulted in a perfect PPV and moderate NPV. Utilizing MSRSGC results in a higher nondiagnostic rate due to the inclusion of cases with benign elements or cyst contents only in this category. Performing ROSE is more important in attaining an adequate sample than the specialty of the person performing SGFNA. K E Y W O R D Sfine-needle aspiration, Milan system for reporting salivary gland cytopathology, salivary gland

Extra-axial ependymomas are very rare but have been reported in the ovary, broad ligament, sacrococcygeal region, lung, and mediastinum. The histogenesis is obscure, and a thorough immunohistochemical analysis is lacking. We reviewed the morphologic and immunohistochemical features of 5 extra-axial ependymomas occurring in adults, 1 arising in an infantile sacrococcygeal teratoma, and a control group of 10 central nervous system (CNS) ependymomas in adults. All cases were evaluated for expression of epithelial membrane antigen, estrogen receptor (ER), progesterone receptor (PR), WT1, CD99, CK18, AE1:3, CAM 5.2, 34betaE12, CK7, CK20, synaptophysin, chromogranin, and glial fibrillary acidic protein (GFAP) using formalin-fixed, paraffin-embedded tissue. One hundred twelve ovarian carcinomas in 3 tissue microarrays were also studied with GFAP. The adult extra-axial cases demonstrated more architectural variability than the CNS cases. We observed that both the CNS and adult extra-axial ependymomas expressed GFAP diffusely, whereas only 9 stage III, high-grade ovarian serous papillary carcinomas stained with GFAP (2 strongly and diffusely and 7 exhibiting focally weak expression). There were significant immunophenotypic differences between adult extra-axial and CNS ependymomas, with extra-axial cases preferentially expressing 34betaE12 (60% vs. 0%), CK18 (100% vs. 20%), CAM 5.2 (60% vs. 10%), CK7 (80% vs. 10%), ER (100% vs. 10%), and PR (80% vs. 20%). Two spinal cord ependymomas expressed CK18, 1 expressed CK7, and 1 expressed CAM 5.2. CNS ependymomas more frequently expressed CD99 (100% vs. 20%). The following stains were not differentially expressed: epithelial membrane antigen (expressed in 2 of 15 cases, including both extra-axial and CNS ependymomas), synaptophysin (1/15), chromogranin (0/15), WT1 (8/15), AE1:3 (10/15), and CK20 (0/15). The ependymal elements of the sacrococcygeal tumor failed to express 34betaE12, CK18, CAM 5.2, and CK7, like most CNS ependymomas. The morphologic and immunophenotypic differences between extra-axial and CNS ependymomas suggest that they derive from distinct precursors and/or differentiate along distinct pathways. The differential diagnosis of extra-axial ependymomas is extensive, and GFAP expression in primary ovarian serous carcinomas, although rare, could theoretically contribute to diagnostic difficulties. ER and PR expression in extra-axial ependymomas may provide targets for hormonal therapy.

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Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare biphasic tumor of the thyroid with approximately 20 well-documented cases reported in the English literature. Although a monophasic variant of SETTLE is conceivable, the majority of the reported cases were truly biphasic tumors. A minimal amount of epithelial component was present in the reported cases of so-called spindle-cell predominant SETTLE. Here, we report an apparently monophasic case of SETTLE in a 16-yr-old girl, in which no epithelial cells were identified in either fine-needle aspiration biopsy (FNAB) or the subsequent hemithyroidectomy specimen. The FNAB smears were moderately cellular and composed of single and loosely grouped spindle cells with homogenous metachromatic material, which could be mistaken as amyloid, erroneously suggesting medullary thyroid carcinoma. The compact nodules of uniform spindle cells in histology sections raised the possibility of monophasic synovial sarcoma. The spindle cells stained positive for both cytokeratin and vimentin, but were negative for thyroglobulin and calcitonin as well as neuroendocrine markers, confirming the diagnosis of SETTLE.

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