Usama Sajjad

Ziyu Su, Mostafa Rezapour, Usama Sajjad et al.

Multiple instance learning (MIL) models have achieved remarkable success in analyzing whole slide images (WSIs) for disease classification problems. However, with regard to gigapixel WSI classification problems, current MIL models are often incapable of differentiating a WSI with extremely small tumor lesions. This minute tumor-to-normal area ratio in a MIL bag inhibits the attention mechanism from properly weighting the areas corresponding to minor tumor lesions. To overcome this challenge, we propose salient instance inference MIL (SiiMIL), a weakly-supervised MIL model for WSI classification. Our method initially learns representations of normal WSIs, and it then compares the normal WSIs representations with all the input patches to infer the salient instances of the input WSI. Finally, it employs attention-based MIL to perform the slide-level classification based on the selected patches of the WSI. Our experiments imply that SiiMIL can accurately identify tumor instances, which could only take up less than 1% of a WSI, so that the ratio of tumor to normal instances within a bag can increase by two to four times. It is worth mentioning that it performs equally well for large tumor lesions. As a result, SiiMIL achieves a significant improvement in performance over the state-of-the-art MIL methods.

Ziyu Su, Mostafa Rezapour, Usama Sajjad et al.

Although multiple instance learning (MIL) methods are widely used for automatic tumor detection on whole slide images (WSI), they suffer from the extreme class imbalance within the small tumor WSIs. This occurs when the tumor comprises only a few isolated cells. For early detection, it is of utmost importance that MIL algorithms can identify small tumors, even when they are less than 1% of the size of the WSI. Existing studies have attempted to address this issue using attention-based architectures and instance selection-based methodologies, but have not yielded significant improvements. This paper proposes cross-attention-based salient instance inference MIL (CASiiMIL), which involves a novel saliency-informed attention mechanism, to identify breast cancer lymph node micro-metastasis on WSIs without the need for any annotations. Apart from this new attention mechanism, we introduce a negative representation learning algorithm to facilitate the learning of saliency-informed attention weights for improved sensitivity on tumor WSIs. The proposed model outperforms the state-of-the-art MIL methods on two popular tumor metastasis detection datasets, and demonstrates great cross-center generalizability. In addition, it exhibits excellent accuracy in classifying WSIs with small tumor lesions. Moreover, we show that the proposed model has excellent interpretability attributed to the saliency-informed attention weights. We strongly believe that the proposed method will pave the way for training algorithms for early tumor detection on large datasets where acquiring fine-grained annotations is practically impossible.

Tianyang Wang, Ziyu Su, Abdul Rehman Akbar et al.

Vision foundation models (VFMs), such as DINOv3, provide rich semantic representations that are promising for computational pathology. However, many current adaptations pair frozen VFMs with lightweight decoders, creating a capacity mismatch that often limits boundary fidelity for infiltrative tumor bulk segmentation. This paper presents Dino-NestedUNet, a framework that couples a pre-trained DINOv3 encoder with a Nested Dense Decoder. Instead of sparse skip connections and linear upsampling, the proposed decoder forms a dense grid of intermediate pathways to enable continuous feature reuse and multi-scale recalibration, aligning high-level semantics with low-level morphological textures during reconstruction. We evaluate Dino-NestedUNet on three histopathology cohorts (multi-center CHTN, institutional OSU, and CAMELYON16) and observe consistent improvements over UNet++ and standard Dino-UNet variants, particularly under cross-domain shift. To further assess external generalization, we perform zero-shot evaluation by training on CHTN and directly testing on unseen TIGER WSIBULK and OSU CRC cohorts without fine-tuning. These results suggest that dense decoding is a key ingredient for unlocking foundation encoders in boundary-sensitive pathology segmentation.

Hikmat Khan, Usama Sajjad, Metin N. Gurcan et al.

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Accurate survival prediction is essential for treatment stratification, yet existing pathology foundation models often overlook organ-specific features critical for CRC prognostication. Methods: We propose MorphDistill, a two-stage framework that distills complementary knowledge from multiple pathology foundation models into a compact CRC-specific encoder. In Stage I, a student encoder is trained using dimension-agnostic multi-teacher relational distillation with supervised contrastive regularization on large-scale colorectal datasets. This preserves inter-sample relationships from ten foundation models without explicit feature alignment. In Stage II, the encoder extracts patch-level features from whole-slide images, which are aggregated via attention-based multiple instance learning to predict five-year survival. Results: On the Alliance/CALGB 89803 cohort (n=424, stage III CRC), MorphDistill achieves an AUC of 0.68 (SD 0.08), an approximately 8% relative improvement over the strongest baseline (AUC 0.63). It also attains a C-index of 0.661 and a hazard ratio of 2.52 (95% CI: 1.73-3.65), outperforming all baselines. On an external TCGA cohort (n=562), it achieves a C-index of 0.628, demonstrating strong generalization across datasets and robustness across clinical subgroups. Conclusion: MorphDistill enables task-specific representation learning by integrating knowledge from multiple foundation models into a unified encoder. This approach provides an efficient strategy for prognostic modeling in computational pathology, with potential for broader oncology applications. Further validation across additional cohorts and disease stages is warranted.

Tianyang Wang, Ziyu Su, Abdul Rehman Akbar et al.

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.

Usman Afzaal, Ziyu Su, Usama Sajjad et al.

Reproducibility remains a critical challenge in foundation model training for histopathology, often hindered by software randomness, hardware non-determinism, and inconsistent hyperparameter reporting. To investigate these issues, we trained a CLIP model on the QUILT-1M dataset and systematically evaluated the impact of different hyperparameter settings and augmentation strategies across three downstream histopathology datasets (PatchCamelyon, LC25000-Lung, and LC25000-Colon). Despite variability across runs, we identified clear trends: RandomResizedCrop values of 0.7-0.8 outperformed more aggressive (0.6) or conservative (0.9) settings, distributed training without local loss improved stability, and learning rates below 5.0e-5 consistently degraded performance across all datasets. The LC25000 (Colon) dataset consistently provided the most reproducible benchmark. These findings highlight that reproducibility in computational pathology depends not only on transparent documentation but also on carefully chosen experimental configurations, and we provide practical rules to guide future efforts in developing reproducible foundation models for digital pathology.

Usama Sajjad, Abdul Rehman Akbar, Ziyu Su et al.

Colorectal cancer (CRC) remains the third most prevalent malignancy globally, with approximately 154,000 new cases and 54,000 projected deaths anticipated for 2025. The recent advancement of foundation models in computational pathology has been largely propelled by task agnostic methodologies that can overlook organ-specific crucial morphological patterns that represent distinct biological processes that can fundamentally influence tumor behavior, therapeutic response, and patient outcomes. The aim of this study is to develop a novel, interpretable AI model, PRISM (Prognostic Representation of Integrated Spatial Morphology), that incorporates a continuous variability spectrum within each distinct morphology to characterize phenotypic diversity and reflecting the principle that malignant transformation occurs through incremental evolutionary processes rather than abrupt phenotypic shifts. PRISM is trained on 8.74 million histological images extracted from surgical resection specimens of 424 patients with stage III CRC. PRISM achieved superior prognostic performance for five-year OS (AUC = 0.70 +- 0.04; accuracy = 68.37% +- 4.75%; HR = 3.34, 95% CI = 2.28-4.90; p < 0.0001), outperforming existing CRC-specific methods by 15% and AI foundation models by ~23% accuracy. It showed sex-agnostic robustness (AUC delta = 0.02; accuracy delta = 0.15%) and stable performance across clinicopathological subgroups, with minimal accuracy fluctuation (delta = 1.44%) between 5FU/LV and CPT-11/5FU/LV regimens, replicating the Alliance cohort finding of no survival difference between treatments.

Ziyu Su, Abdul Rehman Akbar, Usama Sajjad et al.

Foundation models (FM) have transformed computational pathology but remain computationally prohibitive for clinical deployment due to their massive parameter counts and high-magnification processing requirements. Here, we introduce XMAG, a lightweight FM developed through corss-magnification distillation that transfers knowledge from state-of-the-art 20x magnification teacher to an efficient 5x magnification student architecture. XMAG employs a compact backbone and operates entirely at 5x, requiring 11.3 times fewer patches per whole slide image (WSI) compared to existing approaches. Our Novel distillation framework incorporates dual-level knowledge transfer, aligning both global image representations and local spatial token mapping. We trained XMAG on 3.49 million images curated from publicly available datasets and evaluated performance across six clinically relevant histopathology analysis tasks spanning multiple cancer types. XMAG achieved diagnostic accuracy within 1% of substantially larger foundation models while delivering 30-fold processing acceleration, reaching 8.8 WSIs per minute processing speed. Our cross-institutional validation confirmed robust generalization. Further, we developed an end-to-end training strategy to further boost our model's performance to approach the larger FMs' performance. These results establish cross-magnification distillation as a viable approach for deploying FM capabilities in resource-constrained clinical environments, potentially enabling real-time pathology AI integration.

Abdul Rehman Akbar, Usama Sajjad, Ziyu Su et al.

Despite surgical resection, ~70% of invasive lung adenocarcinoma (ILA) patients recur within five years, and current tools fail to identify those needing adjuvant therapy. To address this unmet clinical need, we introduce CellEcoNet, a novel spatially aware deep learning framework that models whole slide images (WSIs) through natural language analogy, defining a "language of pathology," where cells act as words, cellular neighborhoods become phrases, and tissue architecture forms sentences. CellEcoNet learns these context-dependent meanings automatically, capturing how subtle variations and spatial interactions derive recurrence risk. On a dataset of 456 H&E-stained WSIs, CellEcoNet achieved superior predictive performance (AUC:77.8% HR:9.54), outperforming IASLC grading system (AUC:71.4% HR:2.36), AJCC Stage (AUC:64.0% HR:1.17) and state-of-the-art computational methods (AUCs:62.2-67.4%). CellEcoNet demonstrated fairness and consistent performance across diverse demographic and clinical subgroups. Beyond prognosis, CellEcoNet marks a paradigm shift by decoding the tumor microenvironment's cellular "language" to reveal how subtle cell variations encode recurrence risk.