Multimodal large language models (MLLMs) have shown great potential in medical applications, yet existing benchmarks inadequately capture real-world clinical complexity. We introduce MEDSYN, a multilingual, multimodal benchmark of highly complex clinical cases with up to 7 distinct visual clinical evidence (CE) types per case. Mirroring clinical workflow, we evaluate 18 MLLMs on differential diagnosis (DDx) generation and final diagnosis (FDx) selection. While frontier models often match or even outperform human experts on DDx generation, all MLLMs exhibit a much larger DDx–FDx performance gap compared to expert clinicians, indicating a failure mode in synthesis of heterogeneous CE types. Ablations attribute this failure to (i) overreliance on less discriminative textual CE (e.g., medical history) and (ii) a cross-modal CE utilization gap. We introduce Evidence Sensitivity to quantify the latter and show that a smaller gap correlates with higher diagnostic accuracy. Finally, we demonstrate how it can be used to guide interventions to improve model performance. https://github.com/jianing-lab/MEDSYN.

Conformal prediction (CP) is a distribution-free framework for uncertainty quantification that has recently been adapted to large language models (LLMs), providing prediction sets with finite-sample coverage guarantees under exchangeability. Yet for LLMs, nonconformity scores are often induced by an inference pipeline, not just a fixed model, making them depend not only on the data distribution but also on configurable factors such as the prompt template, decoding parameters, and deployment setting. Since such configurations are routinely modified in practice but rarely treated as a source of shift, their impact on CP validity remains poorly understood. We call this configuration shift and study it systematically along three axes: prompt template, decoding temperature, and weight quantization. In a broad empirical study spanning 9 LLMs, 4 datasets, and 4 nonconformity scores, we find that configuration shift consistently erodes CP validity, often driving empirical coverage below the target. By contrast, efficiency is largely preserved: valid prediction sets remain close in size to the i.i.d. baseline. We derive coverage lower bounds that attribute this loss to a discrepancy between calibration and test score distributions, and use their finite-sample plug-in versions as empirical diagnostics of shift severity. We further show that these findings lead to practical mitigations: bound-inspired recalibration is effective with limited test examples, while fragility-aware calibration ensembling recovers much of the lost coverage without test data.