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Human epidermal growth factor receptor 2 ( HER2 ) gene amplification and subsequent protein overexpression is a strong prognostic and predictive biomarker in invasive breast carcinoma (IBC). ASCO/CAP recommended tests for HER2 assessment include immunohistochemistry (IHC) and/or in situ hybridization (ISH). Accurate HER2 IHC scoring (0, 1+, 2+, 3+) is key for appropriate classification and treatment of IBC. HER2-targeted therapies, including anti-HER2 monoclonal antibodies and antibody drug conjugates (ADC), have revolutionized the treatment of HER2-positive IBC. Recently, ADC have also been approved for treatment of HER2-low (IHC 1+, IHC 2+/ISH-) advanced breast carcinoma, making a distinction between IHC 0 and 1+ crucial. In this focused study, 32 IBC with HER2 IHC scores from 0 to 3+ and HER2 FISH results formed a calibration dataset, and 77 IBC with HER2 IHC score 2+ and paired FISH results (27 amplified, 50 non-amplified) formed a validation dataset. H&E and HER2 IHC whole slide images (WSI) were scanned. Regions of interest were manually annotated and IHC scores generated by the software QuantCenter (MembraneQuant application) by 3DHISTECH Ltd. (Budapest, Hungary) and compared to the microscopic IHC score. H-scores [(3×%IHC3+) +(2×%IHC2+) +(1×%IHC1+)] were calculated for semi-automated (MembraneQuant) analysis. Concordance between microscopic IHC scoring and 3DHISTECH MembraneQuant semi-automated scoring in the calibration dataset showed a Kappa value of 0.77 (standard error 0.09). Microscopic IHC and MembraneQuant image analysis for the detection of HER2 amplification yielded a sensitivity of 100% for both and a specificity of 56% and 61%, respectively. In the validation set of IHC 2+ cases, only 13 of 77 cases (17%) had discordant results between microscopic and MembraneQuant images, and various artifacts limiting the interpretation of HER2 IHC, including cytoplasmic/granular staining and crush artifact were noted. Semi-automated analysis using WSI and microscopic evaluation yielded similar HER2 IHC scores, demonstrating the potential utility of this tool for interpretation in clinical practice and subsequent accurate treatment. In this study, it was shown that semi-automatic HER2 IHC interpretation provides an objective approach to a test known to be quite subjective., Competing Interests: FP is a member of the scientific advisory board of Multiplex DX. In addition, FP serves on the diagnostic advisory board and reports receiving consultancy fees from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liao, Bakoglu, Cesmecioglu, Hanna, Pareja, Wen, D’Alfonso, Brogi, Yagi and Ross.)

In colorectal carcinoma (CRC), tumor deposits (TDs) are described as macroscopic/microscopic nests/nodules in the lymph drainage area discontinuous with the primary mass, without identifiable lymph node (LN) tissue, and not confined to vascular or perineural spaces. A TD is categorized as pN1C only when no bona fide LN metastasis exists. However, there has been an ongoing debate on whether TDs should be counted as LNs. The fact that the origin of TDs is not fully understood adds further uncertainty. This pilot study aims to evaluate whether whole-block imaging by micro-computed tomography (micro-CT WBI) that enables three-dimensional reconstruction of whole-mount (WM) blocks can serve as a tool to assess the origin and path of CRC TDs. We evaluated whole-slide imaging (WSI) and micro-CT WBI of 20 WM blocks from a rectal cancer resection that contained TDs. Each TD was tracked through the contiguous blocks to define their origin and path. Of eleven TDs identified on WSI, six were detected on WBI. Strikingly, six of six TDs trackable through the blocks on WBI revealed an origin from the main tumor. This pilot study provided evidence that micro-CT WBI can serve as an effective tool to evaluate the origin and path of CRC TDs.