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Reconstructing virtual large slides can improve the accuracy and consistency of tumor bed evaluation for breast cancer after neoadjuvant therapy | Diagnostic Pathology


Tumor bed evaluation in post-NAT breast cancer often requires stacking and assembling multiple slides to measure the maximum diameter of the tumor bed. However, this is an inconvenient process, and holding the stack stable is difficult when there are too many slides involved. Furthermore, each physician may have different stacking order, which will not only lead to differences in the final stitched image but also different measurements for the length and width of the tumor bed, ultimately affecting the accuracy of the final RCB index and T staging. Therefore, pathologists have made several attempts at solving this problem. On one hand, large-section histopathology (LSH) produces large sections (7.5 cm × 5 cm × 5 μm), which allows the observation the entire excised tissue without the tissue fragments stitching process. The LSH was first reported in 1994 by Jackson et al. [22], and subsequently applied to esophageal cancer [23], liver cancer [24], breast cancer [25], prostate cancer [26], and so on. However, since the LSH has a size limitation of 7.5 cm by 5 cm, it is not suitable for larger specimens. On the other hand, the promotion of LSH is limited by a variety of reasons such as the high level of operational difficulty, long cycle of slide preparation, complicated procedures, high costs, and poor slide quality.

On the other hand, WSI fragments stitching programs are developed for the reconstruction of VLS [12,13,14]. We also independently developed a stitching software for pathological tissue fragments – the WSI Stitcher. It allows the import, rotation, flipping and panning of multiple WSI images to reconstruct gross specimens. This software enables rapid and convenient reconstruction and measurement of VLS and saves the high cost and the tedious work of dehydrating, sectioning and staining required by LSH. Moreover, WSI stitcher can help pathologists to get more accurate pathological measurements, thus facilitating RCB grading for the evaluation of NAT outcomes, and providing guidance for the formulation of subsequent treatment plans.

Our study indicates that compared with the conventional method, the time required for all pathologists to perform tumor bed evaluation in post-NAT breast cancer with the assistance of WSI Stitcher was significantly shorter (P < 0.001)(Fig. 4). In the conventional evaluation method, the stacking of more slides makes the tissue area easier obscured by the slide label(Fig. 3a,c). Therefore, pathologists need to try repeatedly before finding a suitable placement and stacking position. This process is very time-consuming. In contrast, with WSI stitcher, pathologists can quickly restore and stitch WSI fragments by referring the cut record on X-ray.

In the tumor bed evaluation process, when using the conventional evaluation method to determine the length and width of the tumor bed, the percentage of residual tumor cells and the percentage of DCIS, the ICC values of five pathologists were 0.934, 0.927, 0.878 and 0.881, respectively. When performing WSI Stitcher-assisted evaluation, the ICC values were 0.994, 0.992, 0.947 and 0.983, respectively. As the number of slides increases, the ICC of the conventional method is declining, indicating that the stitching and measurement difficulty increases with the slide amount. The software-assisted splicing method overcomes this difficulty and remains high tumor bed evaluation consistency as slide amount increases(Fig. 5a-d). We believe the higher ICC is caused by two main reasons. First, in the stitching phases, as we can find in Fig. 3, the final stitching result of conventional methods can be different for everyone. However, with the help of WSI stitcher, the stitching results are almost the same. In the measuring phase, WSI stitcher provides pixel-level measurement accuracy. In contrast, the conventional approach using a ruler for measurements on the stack slides is very rough.

Furthermore, the WSI stitcher can automatically display the percentage of residual tumor cells and the percentage of DCIS once the tumor margin is labeled. These features can effectively enhance the accuracy and efficiency of tumor bed evaluation in post-NAT breast cancer. Therefore, WSI Stitcher exhibited significant advantages in tumor bed evaluation. Compared with conventional evaluation methods, the consistency of pathologists using software assisted methods to evaluate tumor stage, RCB index and RCB grading was significantly improved (p<0.001).

Based on clinical experience, we believe that the gold standard for tumor bed evaluation in post-NAT breast cancer is the complete tumor bed obtained using a large-section microtome. Since the complete tumor bed is preserved, there is no need for stitching, nor are there issues of interference from gaps or alignment, and hence this approach should be considered the gold standard that is closest to the true state of the specimen. However, due to time and manpower constraints, we were unable to conduct further research based on the gold standard. Nevertheless, given the various advantages and practicalities of software-assisted stitching, we also believe WSI Stitcher-assisted stitching is an evaluation method that is closer to the gold standard than conventional manual stitching. Thus, it can effectively enhance the accuracy of tumor bed evaluation in post-NAT breast cancer.

In addition, the saved high-quality slides can be used to for future analysis, for example, artificial intelligence-assisted interpretation of indicators such as TILs. Investigations have shown that the tumor regression grade of post-NAT breast cancer [27] is significantly correlated with prognosis, and the emergence of large sections can assist physicians in better evaluating these crucial pathological features. Furthermore, the construction of a WSI database for the patient’s tumor bed can facilitate the easy extraction of saved high-quality large sections of the tumor bed, which can be compared with H&E slides from preoperative needle biopsy, and possible recurrent or metastatic lesions in the future. This will prevent inconsistencies in the tumor bed caused by multiple rounds of manual overlay and stitching. There are broad application prospects for the construction of a tumor bed WSI database in post-NAT breast cancer. It will lay a solid foundation for further in-depth examinations on the pathological morphology of the tumor bed in post-NAT breast cancer, while the preservation of patient information will substantially facilitate repeat examinations of pathological features and future scientific research. This will be of great significance to the patient’s personalized precision treatment and long-term follow-up.

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