Practical guidelines for multiple instance learning in computational pathology: how embedding choice impacts overall survival prediction

Whole Slide Images (WSIs) are a core data modality in computational pathology, yet their gigapixel resolution requires weakly supervised approaches such as Multiple Instance Learning (MIL) for prognostic modeling. While recent advances in representation learning have introduced domain-specific and foundation models for histopathology, it remains unclear how the choice of patch-level embedding influences survival prediction performance when combined with different MIL architectures and applied across heterogeneous cancer cohorts. Systematic evaluations addressing this gap are still limited. In this work, we present a comprehensive benchmark aimed at deriving practical guidelines for MIL-based Overall Survival (OS) prediction from WSIs. We compare four representative tile embedding strategies (ResNet50, ProvGigaPath, UNI, and CONCH) across five The Cancer Genome Atlas (TCGA) cohorts: bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD) and one dataset from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), clear cell renal cell carcinoma (ccRCC). Patch-level features are aggregated using three state-of-the-art MIL survival models: Attention-Based MIL (ABMIL), Transformer-based MIL (TransMIL), and Dual-Stream MIL (DSMIL). Furthermore, the analysis is extended to include a comparison with two state-of-the-art slide-level encoders, TITAN and the ProvGigaPath slide encoder, utilizing a Cox Proportional Hazard (CPH) model as the prediction head to benchmark patch-aggregation approaches against end-to-end slide representations. Prognostic performance is assessed using the concordance index (c-index), with interpretability evaluated through risk stratification analysis. Our results show that embedding choice has a substantial and consistent impact on OS prediction accuracy, robustness, and interpretability across cancer types, with domain-specific and foundation models outperforming conventional convolutional baselines. These findings provide evidence-based practical guidelines for designing robust and generalizable WSI-based survival prediction pipelines in computational pathology.