Semantic Integrative Digital Pathology . Insights on micro-semiological semantics and image analysis scalability

Being able to provide traceable and dynamic second opinion has become an ethical priority for patients and healthcare professionals in modern computer aided medicine. In this perspective, a semantic cognitive virtual microscopy approach has been initiated1, by focusing on digital pathology. This approach supports the elaboration of pathology-compliant daily protocols dedicated to breast cancer grading, in particular mitotic count and nuclear atypia. A proof of concept has so been elaborated and an extension of these approaches is now on going under a collaborative digital pathology framework2. Important milestone on the way to routine Digital Pathology, a series of pioneer international benchmarking initiatives have been launched for mitosis detection3, nuclear atypia grading4 and glandular structures detection5 some of the fundamental grading components in diagnosis / prognosis. These initiatives allow envisaging a consolidated validation referential-database for Digital Pathology in the very near future. This reference database will need coordinated efforts from all major teams working in this area worldwide, and will certainly represent a milestone for the acceptance of all future imaging modules in clinical routine. In line with recent advances of molecular imaging and genetics, keeping the microscopic modality at the core of the future digital systems in pathology is fundamental to insure the acceptance of these new technologies, as for a deeper systemic, structured comprehension of the pathologies. After all, at the scale of routine Whole Slide Image (WSI) (around 0.22 μm per pixel), the microscopical image represents a structured "genomic cluster", enabling ⇤Corresponding author, E-mail: daniel.racoceanu@upmc.fr 1MICO project (COgnitive MIcroscopy) French National Research Agency Technologies for Health and Autonomy (ANR TecSan): http://daniraco.free. fr/projects.htm 2FlexMIm project (Collaborative Pathology) Consolidated Interministerial Fund (FUI Fonds Unique Interministériel) : http://www.systematic-paris-region.org/en/projets/flexmim 3Mitosis detection challenges: MITOS @ Int. Conf. Pattern Recognition (ICPR) Tsukuba, Japan, 2012: http://ludo17.free. fr/mitos_2012/ and AMIDA @ Int. Conf. Medical Image Computing and Computer Assisted Intervention (MICCAI) Osaka, Japan, 2013 4Mitosis detection and nuclear atypia grading challenge: MITOS&ATPIA @ Int. Conf. Pattern Recognition (ICPR) Stockholm, Sweden, 2014: http://mitos-atypia-14.grand-challenge.org/ 5Glandular structures detection challenge: GlaS @ Int. Conf. Medical Image Computing and Computer Assisted Intervention (MICCAI) Munich, Germany, 2015 Preprint submitted to Pathobiology January 11, 2016 a naturally structured integration of these heterogeneous data, a natural stuctured support for Integrative Digital Pathology (IDP) approaches. In order to support this integration, as to structure the integration these heterogeneous information, a major effort is and will continue to be devoted to morphological microsemiology (microscopical morphology semantics). Beside supporting the traceability of the results and the orchestration of high-content image analysis modules, the role of semantics will be crucial in the correlation between digital pathology and non-invasive medical imaging modalities, as in defining models able to make the link between traditional microscopy and recent label free technologies. The challenge of massive visual data represents an obvious characteristic of Digital Pathology. Designing an operational integrative microscopy framework, needs to focus on scalable multi-scale imaging formalism. In this sense, we prospectively consider some of the most recent scalable methodologies adapted in Digital Pathology as Marked Point Process for nuclear atypia and Point-set Mathematical Morphology for architecture grading. Orchestrator of this scalable framework, the semantic-based WSI management (analysis, exploration, indexing, retrieval, report generation support) represents an important mean towards integrative big biomedical data approaches. This insight reflects our vision, through an instantiation of essential bricks of this type of architecture. The generic approach introduced here is applicable for number of challenges related to molecular imaging, high content image management as, more generally, to bioinformatics.