A Lightweight Multi-Cancer Tumor Localization Framework for Deployable Digital Pathology

The expanding ecosystem of pathology foundation models has produced powerful but fragmented tile-level representations, limiting their use in clinical tasks that require unified slide-level reasoning and interpretable linkage to clinically meaningful information. We present ASTRA, a pan-cancer framework that integrates heterogeneous foundation-model representations into a shared slide-level representation space and semantically grounds that space using structured pathology annotation fields, including classification category, cancer type, and anatomic site. ASTRA combines sparse mixture-of-experts contextualization, masked multi-model reconstruction, and contrastive alignment to structured pathology prompts to learn slide representations that support 4-category classification, 3-class solid tumor typing, 16-class cancer typing, and text-guided tumor localization without pixel-level supervision. Developed on a CHTN cohort of 10,359 whole-slide images (WSIs) spanning 16 tumor types, ASTRA consistently improves pan-cancer classification across four pathology foundation-model backbones, achieving up to 97.8% macro-AUC for 4-category classification, 99.7% for 3-class solid tumor typing, and 99.2% for 16-class cancer typing. For tumor localization, ASTRA achieves a mean Dice of 0.897 on an annotated in-domain CHTN subset (n = 380) spanning 16 cancer types and 0.738 on an external TCGA cohort (n = 1,686) spanning four cancer types. These results demonstrate that minimal structured pathology annotation fields derived from slide-level metadata can provide effective semantic supervision for unified slide representation learning, enabling both pan-cancer prediction and weakly supervised tumor localization within a single framework.

In this study, we proposed a deep Swin-Vision Transformer-based transfer learning architecture for robust multi-cancer histopathological image classification. The proposed framework integrates a hierarchical Swin Transformer with ResNet50-based convolution features extraction, enabling the model to capture both long-range contextual dependencies and fine-grained local morphological patterns within histopathological images. To validate the efficiency of the proposed architecture, an extensive experiment was executed on a comprehensive multi-cancer dataset including Breast Cancer, Oral Cancer, Lung and Colon Cancer, Kidney Cancer, and Acute Lymphocytic Leukemia (ALL), including both original and segmented images were analyzed to assess model robustness across heterogeneous clinical imaging conditions. Our approach is benchmarked alongside several state-of-the-art CNN and transfer models, including DenseNet121, DenseNet201, InceptionV3, ResNet50, EfficientNetB3, multiple ViT variants, and Swin Transformer models. However, all models were trained and validated using a unified pipeline, incorporating balanced data preprocessing, transfer learning, and fine-tuning strategies. The experimental results demonstrated that our proposed architecture consistently gained superior performance, reaching 100% test accuracy for lung-colon cancer, segmented leukemia datasets, and up to 99.23% accuracy for breast cancer classification. The model also achieved near-perfect precision, f1 score, and recall, indicating highly stable scores across divers cancer types. Overall, the proposed model establishes a highly accurate, interpretable, and also robust multi-cancer classification system, demonstrating strong benchmark for future research and provides a unified comparative assessment useful for designing reliable AI-assisted histopathological diagnosis and clinical decision-making.

Pathology foundation models integrated with multiple instance learning achieve competitive accuracy within single-cancer cohorts, yet cross-cancer generalization remains unresolved due to organ-specific histological and architectural differences. In this paper, we propose Conserved Immune Topology (CIT), a lightweight spatial representation for cross-cancer MSI-H prediction that augments foundation-model embeddings with biologically motivated immune descriptors. CIT uses unsupervised clustering to identify immune-associated tiles, then encodes tertiary lymphoid structures, peritumoral immune reactions, multi-scale tumor-infiltrating lymphocyte density, and immune-tumor mixing from frozen foundation-model embeddings and tile coordinates without requiring annotations or target-domain data. The proposed method was evaluated under cross-site and cross-cancer settings using CPTAC-COAD and TCGA-STAD cohorts, which introduce scanner variability, distribution shifts, and organ-specific architectural variations. Zero-shot cross-cancer transfer with CIT increased TransMIL AUC from 0.6627 to 0.7161, an absolute gain of 0.0534 (p=0.003), with consistent improvements across all three MIL aggregators. These results suggest that spatial immune topology provides potentially an organ-invariant representation for MSI-H prediction, supporting cross-cancer generalization of pathology foundation models.