Development and Validation of an AI Foundation Model for CNS Tumor Classification

Central nervous system tumors comprise a highly heterogeneous group of neoplasms with substantial diagnostic complexity. The WHO 2021 Classification of Tumors of the Central Nervous System integrates histology with molecular biomarkers, making accurate diagnosis increasingly dependent on molecular features such as IDH mutation, 1p/19q codeletion, H3 alterations, TERT promoter mutation, and other genomic or epigenomic markers. However, broad implementation of comprehensive molecular testing remains limited in many settings because of cost, turnaround time, technical complexity, and tissue constraints.

This retrospective study will use archived formalin-fixed paraffin-embedded H&E glass slides or existing digital WSIs from approximately 20,000 patients with primary or secondary CNS tumors treated at Huashan Hospital, Fudan University and Shandong Provincial Hospital. Slides will be digitized when necessary, de-identified, quality controlled, segmented for tissue regions, and divided into image patches. Patch-level features will be extracted using pretrained image encoders, including ResNet50, UNI, and CONCH, followed by weakly supervised multiple-instance learning aggregation methods such as attention-based MIL and CLAM.

The primary objective is to develop and internally validate an AI model capable of hierarchical CNS tumor classification, including tumor category, tumor family, and terminal WHO 2021 diagnosis. Secondary objectives are to compare alternative model architectures, evaluate prediction performance for key molecular markers, assess model interpretability with attention mapping, and compare AI-only, pathologist-only, and AI-assisted diagnosis on an internal test subset.

No intervention will be delivered to participants, and no clinical treatment decisions will be based on model outputs during this research stage. All data processing and model development will be conducted on secure in-hospital servers using de-identified data in accordance with institutional ethics approval and data protection procedures. ClinicalTrials.gov defines observational studies as studies in which investigators assess outcomes without assigning interventions, which matches this study design.

Inclusion criteria

• Patients who underwent brain or spinal tumor resection or biopsy at Huashan Hospital Fudan University and Shandong Provincial Hospital.
• Postoperative pathology diagnosis consistent with a primary or secondary central nervous system tumor.
• Availability of archived routine H&E-stained glass slides or existing digital whole-slide image files of adequate quality for analysis.
• Availability of essential de-identified clinical and pathological information, including age, sex, tumor location, and key surgical/pathology records.
• Use of archived data and samples permitted under institutional ethics approval, including waiver of informed consent where applicable.

Exclusion criteria

• Severe slide preparation or scanning artifacts that preclude meaningful computational analysis, including extensive tissue folding, severe bubbles, severe detachment, markedly uneven staining/fading, or severe out-of-focus scanning.
• Insufficient viable tumor tissue or insufficient analyzable tumor area for patch extraction.
• Missing or uncertain pathological diagnosis that cannot be reliably reassigned according to the WHO 2021 CNS tumor classification using available records.
• Cases lacking sufficient clinical, pathological, or molecular information required for core study analyses.
• Other cases determined by the investigators to be unsuitable for algorithm training or evaluation after quality control review.