Different HER2 Protein Expression Profiles Aid in the Histologic Differential Diagnosis Between Urothelial Carcinoma In Situ (CIS) and Non-CIS Conditions (Dysplasia and Reactive Atypia) of the Urinary Bladder Mucosa
Institute of Pathology, HELIOS Clinic Bad Saarow, Germany.American Journal of Clinical Pathology (Impact Factor: 2.51). 12/2011; 136(6):881-8. DOI: 10.1309/AJCPKUZ69LXZGFEA
We evaluated HER2 expression profiles in 32 carcinoma in situ (CIS) and 31 non-CIS conditions (5 dysplasia and 26 reactive atypia) of the urinary bladder mucosa by applying breast cancer scoring rules. In situ hybridization was performed on tissue microarrays to assess HER2 gene amplification status. Our immunoprofiling data disclosed moderate to strong HER2 expression in CIS, including the basal layer of the urothelium, and absent to weak HER2 expression in non-CIS conditions. From the histologic differential diagnostic standpoint, immunostaining for HER2 protein represents a useful adjunct to aid in the delineation between CIS and non-CIS conditions of the bladder mucosa. Pathogenically, aberrant HER2 protein expression in CIS seems to be more commonly associated with polysomy than with gene amplification. From a therapeutic viewpoint, prospective clinical studies should investigate the potential benefit of HER2-targeted therapies in CIS, particularly in cases unresponsive to conventional therapeutic regimens.
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ABSTRACT: We assessed c-MET expression and oncogene amplification in a cohort enrolling 92 surgically treated penile squamous cell carcinomas (PSCCs). A tissue microarray was constructed for c-MET immunohistochemistry (IHC) and chromogenic silver in situ hybridization (SISH). Two independent pathologists evaluated IHC by employing the breast cancer scoring rules, and scored the presence of MET oncogene amplification and/or polysomy-7. Eighty study cases (87%) showed c-MET expression. No study case had MET oncogene amplification, but 42 patients (45.7%) had polysomy-7. Polysomy-7 showed a significant positive correlation with c-MET expression (ρ=0.323, p=0.002). Neither c-MET expression nor polysomy-7 was associated with histopathologic parameters or with cancer-specific survival (median post-surgical follow-up 32 months). Our data suggest that the majority of PSCCs exhibit c-MET expression which is not associated with oncogene amplification, but might be attributable to polysomy-7. Further studies should investigate the expression and activation of downstream molecules functionally involved in c-MET pathway signaling, and clarify the so far unresolved role of c-MET inhibitors as potential targeted therapies in PSCCs with metastatic dissemination.Pathology - Research and Practice 03/2013; 209(4). DOI:10.1016/j.prp.2013.02.002 · 1.40 Impact Factor
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ABSTRACT: Although differentiating reactive urothelial atypia from urothelial carcinoma in situ (CIS) relies primarily on histologic evaluation, confirming the morphologic impression using immunohistochemistry (IHC) has been increasingly used in routine clinical practice. The aims of this study are to confirm the utility of commonly used markers (CK20, P53) and to test the performance of CK5/6, CD138, and Her2/Neu in the diagnosis of CIS. Using a tissue microarray comprising 52 cases of normal/reactive urothelium and 45 cases of CIS, the IHC evaluation of 5 markers was undertaken. Although the individual specificity of CK20, P53, and Her2/Neu was high (94%, 90%, and 93%, respectively), their sensitivity for CIS detection was lower, with the most sensitive marker being HER2/Neu (63%). Whereas 78% of CIS shows positivity of at least 2 of those 3 markers, only 1 case of reactive urothelium shows positivity for 2 of those 3 markers. The discriminatory performance of CK5/6 and CD138 was poor. In conclusion, HER2/Neu can be added to a panel of CK20 and P53 to help differentiate reactive atypia from CIS in difficult cases. Positive staining for at least 2 of the 3 antibodies (CK20, P53, and HER2/Neu) is strongly associated with CIS. However, the histologic findings should be a primary determinant in the diagnosis of flat urothelial lesions, with IHC playing a supportive confirmatory role.Annals of diagnostic pathology 02/2014; 18(1):27-32. DOI:10.1016/j.anndiagpath.2013.10.006 · 1.12 Impact Factor
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ABSTRACT: The bladder working group of the 2013 International Society of Urologic Pathology (ISUP) Conference on Best Practices Recommendation in the Application of Immunohistochemistry (IHC) in Urologic Pathology discussed 5 settings in which IHC is commonly used in clinical practice. With regard to markers for urothelial differentiation, the committee found that there is no ideal marker or established panel to confirm urothelial differentiation. On the basis of the differential diagnostic consideration, positivity for GATA3, CK20, p63, and either high-molecular weight cytokeratin (HMWCK) or cytokeratin (CK)5/6 is of value in proving urothelial differentiation in the appropriate morphologic and clinical context. With regard to the role of IHC in the distinction of reactive atypia from urothelial carcinoma in situ, the committee recommended that morphology remains the gold standard in this differential diagnosis and that, at best, the IHC panel of CK20/p53/CD44(s) has potential utility but is variably used and has limitations. The immunostaining pattern must be interpreted with strict morphologic correlation, because overreliance on IHC may be misleading, particularly in the posttreatment setting. IHC has no role in the distinction of dysplasia versus carcinoma in situ and in the grading of papillary urothelial carcinoma. IHC may have a limited but distinct role in staging of bladder cancer. In a subset of cases, depending on the clinical and histologic context, broad-spectrum cytokeratins (to identify early or obscured invasion) and desmin (distinction of muscle from desmoplasia and to highlight muscle contours for subclassification) may be helpful. Limited experience and conflicting data preclude smoothelin or vimentin to be recommended routinely for subclassifying muscle type at this time. In the workup of a spindled cell proliferation of the bladder and in limited specimens, we recommend an immunohistochemical panel of 6 markers including ALK1, SMA, desmin, cytokeratin (AE1/AE3), and p63 with either of HMWCK or CK5/6. Currently, there are no prognostic immunohistochemical or molecular studies that are recommended to be routinely performed on biopsy or resection specimens.American Journal of Surgical Pathology 08/2014; 38(8):e20-e34. DOI:10.1097/PAS.0000000000000240 · 5.15 Impact Factor
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