Simple SummaryEarly image-based diagnosis is crucial to improve outcomes in pancreatic ductal adenocarcinoma (PDAC) patients, but is challenging even for experienced radiologists. Artificial intelligence has the potential to assist in early diagnosis by leveraging high amounts of data to automatically detect small (<2 cm) lesions. In this study, the state-of-the-art, self-configuring framework for medical segmentation nnUnet was used to develop a fully automatic pipeline for the detection and localization of PDAC lesions on contrast-enhanced computed tomography scans, with a focus on small lesions. Furthermore, the impact of integrating the surrounding anatomy (which is known to be relevant to clinical diagnosis) into deep learning models was assessed. The developed automatic framework was tested in an external, publicly available test set, and the results showed that state-of-the-art deep learning can detect small PDAC lesions and benefits from anatomy information.Early detection improves prognosis in pancreatic ductal adenocarcinoma (PDAC), but is challenging as lesions are often small and poorly defined on contrast-enhanced computed tomography scans (CE-CT). Deep learning can facilitate PDAC diagnosis; however, current models still fail to identify small (<2 cm) lesions. In this study, state-of-the-art deep learning models were used to develop an automatic framework for PDAC detection, focusing on small lesions. Additionally, the impact of integrating the surrounding anatomy was investigated. CE-CT scans from a cohort of 119 pathology-proven PDAC patients and a cohort of 123 patients without PDAC were used to train a nnUnet for automatic lesion detection and segmentation (nnUnet_T). Two additional nnUnets were trained to investigate the impact of anatomy integration: (1) segmenting the pancreas and tumor (nnUnet_TP), and (2) segmenting the pancreas, tumor, and multiple surrounding anatomical structures (nnUnet_MS). An external, publicly available test set was used to compare the performance of the three networks. The nnUnet_MS achieved the best performance, with an area under the receiver operating characteristic curve of 0.91 for the whole test set and 0.88 for tumors <2 cm, showing that state-of-the-art deep learning can detect small PDAC and benefits from anatomy information.