Breast Neoplasms: Barry TS

Vance GH, Barry TS, Bloom KJ, Fitzgibbons PL, Hicks DG, Jenkins RB, Persons DL, Tubbs RR, Hammond ME, Anonymous00034. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Arch Pathol Lab Med. · Pubmed #19391661 No free full text.

Abstract: CONTEXT: Intratumoral heterogeneity of HER2 gene amplification has been well documented and represents subclonal diversity within the tumor. The reported incidence of intratumor HER2 amplification genetic heterogeneity ranges in the literature from approximately 5% to 30%. The presence of HER2 genetic heterogeneity may increase subjectivity in HER2 interpretation by the pathologist. OBJECTIVES: To define HER2 genetic heterogeneity and to provide practice guidelines for examining and reporting breast tumors with genetic heterogeneity for improvement of HER2 testing in breast cancer. DESIGN: We convened an expert panel to discuss HER2 gene amplification testing by fluorescence in situ hybridization. Components addressed included a definition of HER2 amplification heterogeneity, practice guidelines for examination of the tissue, and reporting criteria for this analysis. RESULTS: Genetic heterogeneity for amplification of HER2 gene status in invasive breast cancer is defined and guidelines established for assessing and reporting HER2 results in these cases. These guidelines are additive to and expand those published in 2007 by the American Society of Clinical Oncology and the College of American Pathologists. CONCLUSION: Standardized methods for analysis will improve the accuracy and consistency of interpretation of HER2 gene amplification status in breast cancer.

Yaziji H, Taylor CR, Goldstein NS, Dabbs DJ, Hammond EH, Hewlett B, Floyd AD, Barry TS, Martin AW, Badve S, Baehner F, Cartun RW, Eisen RN, Swanson PE, Hewitt SM, Vyberg M, Hicks DG, Anonymous00020. · Vitro Molecular Laboratories, Miami, FL daggerKeck School of Medicine, University of Southern California, Los Angeles, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #18931614 No free full text.

Abstract: Estrogen receptor (ER) status in breast cancer is currently the most important predictive biomarker that determines breast cancer prognosis after treatment with endocrine therapy. Although immunohistochemistry has been widely viewed as the gold standard methodology for ER testing in breast cancer, lack of standardized procedures, and lack of regulatory adherence to testing guidelines has resulted in high rates of "false-negative" results worldwide. Standardized testing is only possible after all aspects of ER testing--preanalytical, analytical, and postanalytical, have been closely controlled. A meeting of the "ad-hoc committee" of expert pathologists, technologists, and scientists, representing academic centers, reference laboratories, and various agencies, issued standardization testing recommendations, aimed at optimization of clinical ER testing environment, as a step toward improved standardized testing.

Gown AM, Goldstein LC, Barry TS, Kussick SJ, Kandalaft PL, Kim PM, Tse CC. · PhenoPath Laboratories, Seattle, WA 98103, USA. · Mod Pathol. · Pubmed #18487992 No free full text.

Abstract: The American Society of Clinical Oncologists and College of American Pathologists have recently released new guidelines for laboratory testing of HER2 status in breast cancer, which require high levels (95%) of concordance between immunohistochemistry positive (3+) and fluorescence in situ hybridization-amplified cases, and between immunohistochemistry negative (0/1+) and fluorescence in situ hybridization-nonamplified cases; these required levels of concordance are significantly higher than those found in most published studies. We tested the hypothesis that a modification of the HER2 immunohistochemistry scoring system could significantly improve immunohistochemistry and fluorescence in situ hybridization concordance. A total of 6604 breast cancer specimens were evaluated for HER2 status by both immunohistochemistry and fluorescence in situ hybridization using standard methodologies. Results were compared when the standard immunohistochemistry scoring system was replaced by a normalized scoring system in which the HER2 score was derived by subtracting the score on the non-neoplastic breast epithelium from that on the tumor cells. Among the 6604 tumors, using a non-normalized immunohistochemistry scoring system, 267/872 (30.6%) of the immunohistochemistry 3+ cases proved to be fluorescence in situ hybridization nonamplified, whereas using the normalized scoring system only 30/562 (5.3%) of immunohistochemistry 3+ cases proved to be 'false positive'. The concordance rate between immunohistochemistry 3+ and fluorescence in situ hybridization-amplified cases using the normalized scoring method was 94.7%, whereas the concordance using the non-normalized method was only 69.4%. Extremely high concordance between immunohistochemistry and fluorescence in situ hybridization assessment of HER2 status in breast cancer is achievable, but to attain this high level of concordance, modification of the FDA-approved immunohistochemistry scoring system is required.

Collins LC, Carlo VP, Hwang H, Barry TS, Gown AM, Schnitt SJ. · Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. · Am J Surg Pathol. · Pubmed #16861972 No free full text.

Abstract: Intracystic papillary carcinomas (IPC) of the breast have traditionally been considered to be variants of ductal carcinoma in situ (DCIS). However, it is not clear if all lesions categorized histologically as IPC are truly in situ carcinomas, or if some such lesions might represent circumscribed or encapsulated nodules of invasive papillary carcinoma. Given that the demonstration of a myoepithelial cell (MEC) layer around nests of carcinoma cells is a useful means to distinguish in situ from invasive carcinomas of the breast in problematic cases, assessment of the presence or absence of a MEC layer at the periphery of the nodules that comprise these lesions could help resolve this issue. We studied the presence and distribution of MEC at the periphery of the nodules of 22 IPC and, for comparison, 15 benign intraductal papillomas using immunostaining for 5 highly sensitive markers that recognize various MEC components: smooth muscle myosin heavy chain, calponin, p63, CD10, and cytokeratin 5/6. All 22 lesions categorized as IPC showed complete absence of MEC at the periphery of the nodules with all 5 markers. In contrast, a MEC layer was detected around foci of conventional DCIS present adjacent to the nodules of IPC. Furthermore, all benign intraductal papillomas, including those of sizes comparable to those of IPC, showed a MEC layer around virtually the entire periphery of the lesion with all 5 MEC markers. In conclusion we could not detect a MEC layer at the periphery of the nodules of any of 22 lesions categorized histologically as IPC. One possible explanation for this observation is that these are in situ lesions in which the delimiting MEC layer has become markedly attenuated or altered with regard to expression of these antigens, perhaps due to their compression by the expansile growth of these lesions within a cystically dilated duct. Alternatively, it may be that at least some lesions that have been categorized as IPC using conventional histologic criteria actually represent circumscribed, encapsulated nodules of invasive papillary carcinoma. Regardless of whether these lesions are in situ or invasive carcinomas, available outcome data indicate that they seem to have an excellent prognosis with adequate local therapy alone. Therefore, we believe it is most prudent to continue to manage patients with these lesions as they are currently managed (ie, similar to patients with DCIS) and to avoid categorization of such lesions as frankly invasive papillary carcinomas. Given our observations, we favor the term "encapsulated papillary carcinoma" over "intracystic papillary carcinoma" for circumscribed nodules of papillary carcinoma surrounded by a fibrous capsule in which a peripheral layer of MEC is not identifiable.

Yaziji H, Battifora H, Barry TS, Hwang HC, Bacchi CE, McIntosh MW, Kussick SJ, Gown AM. · Ancillary Pathways, Miami, FL 33243-0777, USA. · Mod Pathol. · Pubmed #16554731 links to  free full text

Abstract: We evaluated the sensitivity and specificity of 10 monoclonal and two polyclonal antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma (AdCA) using immunohistochemistry (IHC). The antibodies were directed against the mesothelial-associated antigens mesothelin, calretinin, cytokeratin 5, thrombomodulin, Wilms' tumor-1 (WT-1) gene product and HBME-1, and the nonmesothelial antigens Lewis-Y blood group (antibody BG8), MOC-31, BerEp4, CD15, and carcinoembryonic antigen (CEA) family. The 133 tumors evaluated included 65 malignant epithelioid mesotheliomas, 22 lung AdCAs, 27 ovarian serous carcinomas, 24 breast carcinomas, and five gastric carcinomas. Diagnoses were based on clinical, histologic, ultrastructural, and/or IHC findings. Calretinin had the best sensitivity for mesothelioma (95%), followed by HBME-1 (84%), WT-1 (78%), cytokeratin 5 (76%), mesothelin (75%), and vimentin and thrombomodulin (68%). Thrombomodulin had the best specificity for mesothelioma (92%), followed by cytokeratin 5 (89%), calretinin (87%) vimentin (84%), and HBME-1 (45%). When ovarian carcinomas were excluded from the analysis, the specificity of mesothelin and WT-1 for the diagnosis of mesothelioma increased to 90 and 81%, respectively. The sensitivity of the nonmesothelial antigens for AdCA was organ dependent, with BG8 performing best in the breast cancer group (96%), and BerEp4, BG8, MOC-31 performing best in the lung cancer group (100%). The specificity of the nonmesothelial antigens for AdCA was 98% for BG8 and CEA, 97% for CD15, 95% for BerEp4, and 87% for MOC-31. A novel statistical analysis technique employing logic regression analysis identified a three-antibody immunohistochemical panel including calretinin, BG8, and MOC-31, which provided over 96% sensitivity and specificity for distinguishing epithelioid mesothelioma from AdCA.

Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, Gralow JR, Livingston RB, Gown AM. · PhenoPath Laboratories, Seattle, Wash 98103, USA. · JAMA. · Pubmed #15113815 links to  free full text

Abstract: CONTEXT: Testing for HER-2 oncogene in breast cancer has increased because of its role as a prognostic and predictive factor. Some advocate gene testing by fluorescence in situ hybridization (FISH) vs protein testing by immunohistochemistry as the method which most accurately evaluates and predicts response to the anti-HER-2 antibody, trastuzumab. However, critical examination of FISH on a screening basis has yet to be performed. OBJECTIVES: To determine the correlation between FISH and immunohistochemistry results by determining HER-2/neu gene status on tumor sections with indeterminate immunohistochemistry results (2+ score), confirm gene amplification on tumor sections with positive results (3+ score), and verify gene status on tumor sections with negative results (0 or 1+ score). DESIGN, SETTING, AND PATIENTS: A quality control and quality assurance program for HER-2 testing by FISH, which used tumor specimens from 2963 patients (median age, 56 years) with breast cancer received from 135 hospitals and cancer centers in 29 states, was performed at a reference laboratory from January 1, 1999, to May 15, 2003. Every specimen evaluated by FISH was parallel tested with immunohistochemistry tests. MAIN OUTCOME MEASURES: With FISH as the presumed standard testing method, the positive and negative predictive values and sensitivity and specificity of immunohistochemistry were calculated. RESULTS: A total of 3260 clinical HER-2 tests by FISH were performed on 2963 serially referred breast cancer specimens. Of these, 2933 tests were successful and 2913 breast cancer specimens had both FISH and immunohistochemistry results available. With FISH as the standard testing method, the positive predictive value of positive immunohistochemistry score (3+) was 91.6%, and the negative predictive value of negative immunohistochemistry score (0 or 1+) was 97.2%. The sensitivity of immunohistochemistry tests, including tumor sections with scores of 2+ or 3+, was 92.6% and the specificity of immunohistochemistry tests with scores of 3+ was 98.8%. The FISH test had a significantly higher failure rate (5% vs 0.08%) and reagent cost (140 dollars vs 10 dollars), and longer testing (36 hours vs 4 hours) and interpretation times (7 minutes vs 45 seconds) vs immunohistochemistry tests. CONCLUSIONS: A testing algorithm for HER-2 determination is most efficient by using immunohistochemistry as the method of choice, with FISH performed for cancers with indeterminate results (2+ score). Successful quality control and quality assurance programs are a prerequisite for such approaches.