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Recovering this third dimension would enable correlation with in vivo imaging, improve multimodal data integration, and open new doors for three-dimensional quantitative tissue analysis. This study presents the RAPID framework, which tackles this task of registering whole slide images of whole-mount histopathology specimens into a three-dimensional stack. Our proposed framework leverages a DINOv2-pretrained ViT-L14 foundational model to consistently detect anatomical features, which are used to align a stack of unregistered whole slide images (WSIs) to obtain a three-dimensional reconstruction. RAPID is optimized to work with high-resolution WSIs at 0.25\n                    <jats:inline-formula>\n                      <jats:tex-math>$$\\upmu$$<\/jats:tex-math>\n                    <\/jats:inline-formula>\n                    m\/pixel, leading to gigapixel reconstructions that can be used for cell-level downstream tasks. We validate our framework on various external validation sets and find that RAPID obtains an accurate reconstruction in 91.7\u201393.5% of cases, thereby significantly outperforming a current state-of-the-art reconstruction method. Unlike existing methods limited to serial sections, RAPID handles the sparse sampling intervals (3000\u20134000\n                    <jats:inline-formula>\n                      <jats:tex-math>$$\\upmu$$<\/jats:tex-math>\n                    <\/jats:inline-formula>\n                    m) routinely used in clinical pathology. We demonstrate its utility for three-dimensional radiology-pathology correlation, enabling direct volumetric comparison between histopathology and pre-operative imaging.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-46776-4","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:48:50Z","timestamp":1775116130000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Three-dimensional reconstruction of gigapixel whole-mount histopathology specimens with RAPID"],"prefix":"10.1038","volume":"16","author":[{"given":"Daan","family":"Schouten","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen","family":"van der Laak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diederik","family":"Somford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi","family":"K\u00fcsters-Vandevelde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadieh","family":"Khalili","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geert","family":"Litjens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"46776_CR1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.mri.2021.10.008","volume":"85","author":"M Gibbons","year":"2022","unstructured":"Gibbons, M. et al. 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