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Isolated CEP17 Copy Number Gain in Invasive Breast Cancer Results in a “Reverse” Amplification Status

Dual-color silver-enhanced in situ hybridization (SISH) is a well-established method for determining the HER2 gene amplification status in invasive breast cancers with equivocal “2+” HER2 protein expression. Dual-color SISH applies 2 different probes on a single tissue slide: a probe for the HER2 gene and a centromere 17 (CEP17) probe. This technique allows the assessment of the mean HER2 copy number (black dots) and the mean CEP17 copy number (red dots), as well as the calculation of the HER2/ CEP17 ratio. An invasive breast carcinoma is considered to harbor a HER2 gene amplification if the tumor nuclei show a mean HER2 copy number gain of ≥4.0 (ie, on average ≥4.0 black dots per nucleus) and a mean HER2/ CEP17 ratio of ≥2.0.1 An invasive breast carcinoma with a mean HER2 copy number of <4.0 and a mean HER2/ CEP17 ratio of <2.0 is considered nonamplified.1 All other possible scenarios require a correlation with the HER2 immunohistochemistry and, in case of equivocal 2+ HER2 protein expression, recounting of at least 20 nuclei in the area of invasive cancer with 2+ staining by an additional observer blinded for the previous results.1 In this article, we present a breast biopsy containing an invasive carcinoma of no special type with an equivocal 2+ immunohistochemical score (Figure 1). Dual-probe SISH revealed an increased CEP17 copy number in the absence of HER2 gene amplification (Figure 2). After counting 20 nonoverlapping tumor nuclei, the mean CEP17 copy number amounted 7.00 copies per nucleus and the mean HER2 copy number amounted 2.80 copies per nucleus. This isolated CEP17 copy number gain gave the tumor a peculiar image of “reverse” amplification (Figure 2). It was not possible to perform additional array comparative genomic hybridization studies on this tumor; therefore, we cannot differentiate with certainty between a true polysomy 17 or an amplification of the (peri-) centromeric region of chromosome 17 in this lesion. A CEP17 copy number gain has long been attributed to a chromosome 17 polysomy, that is, the presence of multiple copies of the entire chromosome 17.2 However, several studies have now shown that true polysomy 17 is a rather rare event in breast cancer.3-6 An increased CEP17 copy number substantially more often represents a focal pericentromeric gain or so-called “co-amplification” of 911421 IJSXXX10.1177/1066896920911421International Journal of Surgical PathologyVan Bockstal et al research-article2020