Faculty Bibliography

S100 protein is a sensitive marker for melanomas and peripheral nerve sheath tumors. It is, however, expressed by other mesenchymal and epithelial tumors. Despite its low specificity, S100 protein is valuable for the diagnosis of desmoplastic melanomas and peripheral nerve sheath tumors, for which no specific marker is available. Sox10 is a neural crest transcription factor crucial for specification, maturation, and maintenance of Schwann cells and melanocytes. Anti-Sox10 antibody was applied to a variety of neural crest-derived tumors, mesenchymal and epithelial neoplasms, and normal tissues. Sox10 nuclear expression was found in 76 of 78 melanomas (97%) and 38 of 77 malignant peripheral nerve sheath tumors (49%) whereas S100 protein was expressed in 71 melanomas (91%) and 23 malignant peripheral nerve sheath tumors (30%). Sox10 was diffusely expressed in schwannomas and neurofibromas. Sox10 reaction was seen only in sustentacular cells of pheochromocytomas/paragangliomas, and occasionally carcinoid tumors from various organs, but it was not seen in the tumor cells. In normal tissues, Sox10 was expressed in Schwann cells, melanocytes, and myoepithelial cells of salivary, bronchial, and mammary glands. Sox10 reaction was not identified in any other mesenchymal and epithelial tumors except for myoepitheliomas and diffuse astrocytomas. Sox10 was expressed by metastatic melanomas and nodal capsular nevus in sentinel lymph nodes, but not by other lymph node components such as dendritic cells. Our results indicate that Sox10 will serve as a more sensitive and specific marker for the diagnosis of melanocytic and schwannian tumors than S100 protein

The ovary is a common site of involvement for metastasis and the breast is one of the most common sources. Metastatic breast carcinoma can mimic a primary ovarian carcinoma. Pax8 is a crucial transcription factor for organogenesis of the thyroid gland, kidney, and Mullerian system, and it also regulates Wilms tumor suppressor gene (WT1) expression. A total of 124 cases of ovarian carcinomas (84 serous papillary, 18 endometrioid, 12 mucinous, 10 clear cell) and 243 cases of invasive breast carcinomas (178 ductal, 65 lobular) were immunostained with Pax8 and WT1 by tissue microarrays to see the differential expression. Pax8 reaction was found in 108 of 124 ovarian carcinomas (87.1%) generally in diffuse staining, including 81 of 84 serous papillary carcinomas (96.4%), 16 of 18 endometrioid carcinomas (88.9%), 10 of 10 clear cell carcinomas (100%), and 1 of 12 mucinous carcinomas (8.3%), whereas WT1 expression was seen in 78 of 124 ovarian carcinomas (62.9%), including 73 of 84 serous papillary carcinomas (86.9%), and 5 of 18 endometrioid carcinomas (27.8%), with no expression in all 10 clear cell carcinomas and 12 mucinous carcinomas. All the mammary carcinomas were completely negative for Pax8, but WT1 expression was seen in 5 of 243 cases (2.1%). Pax8 is a useful marker in the differential diagnosis of ovarian and breast carcinomas, and it seems to be superior to WT1 for the diagnosis of all types of nonmucinous ovarian carcinomas, notably clear cell and endometrioid types where WT1 expression is generally negative or only focal

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent 'normalization' after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers

Contact sensitizers are a major cause of inflammatory skin disease and as topical immunomodulators also have the potential for treating cancer, viral diseases and certain autoimmune disorders. In the present study, the authors identify the upregulation of the TH17 lymphocyte subset transcription factor retinoid orphan receptor gamma T (RORgammaT) and the CD70 costimulatory pathway in human contact sensitivity (CS) using molecular techniques. Identification of this important new subset of T lymphocytes and a recognized costimulatory pathway offers potential for ameliorating CS and insight into antitumor and antiviral mechanism of haptens as topical immunomodulators

Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3(+) lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3(+) lymphocytes was increased in patients with advanced necroinflammation. CONCLUSION: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection

Foxn1 and CD205 (DEC205) are novel thymic epithelial markers that are important for thymic organogenesis and the positive selection process for thymocytes, respectively. These markers were immunohistochemically applied to a total of 77 cases of thymic epithelial neoplasms comprised of 58 cases of thymomas, 17 cases of thymic carcinomas, and 2 cases of thymic neuroendocrine carcinomas. Foxn1 was diffusely expressed in nuclear staining in all cases of type B thymoma and all but 1 case of type A thymoma, whereas the expression was generally focal in thymic carcinoma (76%). The expression was identified in all cases of mixed AB thymoma, with the expression in type A component being more variable than the one in type B component. CD205 cytoplasmic expression in the form of coarse granular staining with membranous accentuation was strong and diffuse in all cases of type B thymoma (100%), and a majority of type A thymoma (89%), and focal with variable intensity in thymic carcinoma (59%). Mixed AB thymoma demonstrated diffuse expression in type B component (100%), and variable expression in type A component (94%). Neither Foxn1 nor CD205 was expressed in 2 cases of thymic neuroendocrine carcinoma. Foxn1 was focally expressed in 13% of cutaneous squamous cell carcinoma and completely negative in cutaneous basal cell carcinoma, whereas it was completely negative in squamous cell carcinoma from head and neck, esophagus and uterine cervix, and normal tissue and malignant neoplasms from all other organs other than thymus. CD205 was expressed in 4% of nonsmall cell carcinomas of lung, 27% of squamous cell carcinoma of head and neck, and 10% of squamous cell carcinoma of esophagus, but the staining pattern was different from that of thymic epithelial neoplasm and was characterized by rather homogeneous and amorphous quality without granularity or membranous reaction. CD205 was expressed in myeloid dendritic cells of various organs and tissues as well. Foxn1 is a sensitive and specific marker for thymoma and thymic carcinoma, and it appears to be superior to CD5 and CD117 for the diagnosis of thymic carcinoma. CD205 is a sensitive and specific marker for thymoma but its sensitivity to thymic carcinoma is lower than CD5 and CD117.

DC-LAMP is a molecule expressed in mature dendritic cells, but its mRNA is also found in the lung. This study compares the immunostaining spectrum of PE-10, an antisurfactant protein monoclonal antibody; thyroid transcription factor-1 (TTF-1); and DC-LAMP in normal and neoplastic lung in an attempt to characterize the cell type(s) that express DC-LAMP. Electron microscopy was used to define cell types. DC-LAMP marks pulmonary adenocarcinomas that show Clara cell characteristics by electron microscopy. In contrast, PE-10 labels tumors that have Clara cell and type II pneumocyte differentiation. DC-LAMP staining was lost in solid type adenocarcinomas but persisted in well-differentiated areas. CC-10, an antibody that marks Clara cells, was also positive in tumors that labeled for DC-LAMP. There was no prognostic difference in tumors that reacted with DC-LAMP. DC-LAMP and CC-10 reactivity was also observed in endometrial adenocarcinomas but not in other tumor types

Activation of intracellular mitogenic signal transduction pathways driven by the ErbB family of receptor tyrosine kinases has been implicated in the development and/or progression of a variety of cancers. Studies on ErbB receptors in osteosarcoma have focused on HER-2 and have produced conflicting results with few studies evaluating the expression of the epidermal growth factor receptor (EGFR). In this study, we determined the level of expression of EGFR and the mutational status of the EGFR receptor in a subset of osteosarcoma tumor samples as well as in a series of established bone tumor-derived cell lines. EGFR protein expression was detected in the form of strong membranous staining by immunohistochemistry in 21 (57%) of 37 cases analyzed. Six of 12 (50%) osteosarcoma cell lines revealed moderate to high expression levels of EGFR. Two somatic alterations (E829E and R831C) were identified in the cytoplasmic domain of the EGFR gene in 1 of 10 tumor samples. The significance of these findings for the pathobiology of osteosarcomas will be investigated further