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Appl Immunohistochem Mol Morphol. 2012 Dec;20(6):543-9. doi: 10.1097/PAI.0b013e31824d04e8.

HER2/neu gene amplification heterogeneity: the significance of cells with a 3:1 HER2/CEP17 ratio.

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Department of Pathology, University of Utah, USA.


College of American Pathologists published guidelines for the assessment of HER2/neu genetic heterogeneity. When 20 cells are counted for evaluation of HER2/neu amplification, a single 3:1 HER2/CEP17 ratio cell characterizes the sample as heterogneous. Heterogeneity for HER2/neu amplification may indicate biologically important characteristics including likelihood of amplification in metastases. We performed fluorescence in situ hybridization on 1546 cases. For each case, 20 cells of invasive carcinoma were analyzed for HER2/CEP17 ratio. Cases were assessed as nonamplified (ratio<1.8), borderline amplified (1.8 ≤ ratio ≤ 2.2), or amplified (ratio>2.20). Heterogeneity was present when the percentage of cell with ratios >2.20 was ≥5% but <50%. Individual cells were typed by probe ratios and distribution of cell types determined. The distribution of HER2/CEP17 ratio was determined with the number of 3:1 HER2/CEP17 cells plotted against the number of amplified cells. 3:1 HER2/CEP17 ratio cells occur with low frequency (2.2%) but are the determining factor for heterogeneity in 46% of heterogenous cases. Thirty-five percent of heterogenous cases were due to a single 3:1 cell. Single 3:1 cells are a poor predictor for additional amplified cells. Inclusion of cells with a 3:1 HER2/CEP17 ratio in the definition of heterogeneity may be too broad as these cells are the determining factor in approximately one third of diagnoses of heterogeneity but are not strongly associated with other measures of amplification. Moreover, 3:1 HER2/CEP17 ratio cells are a poor predictor for the presence of additional amplified cells in a sample.

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