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Cancer of unknown primary (CUP) origin is an enigmatic group of diagnoses in which the primary anatomical site of tumour origin cannot be determined1,2. This poses a considerable challenge, as modern therapeutics are predominantly specific to the primary tumour3. Recent research has focused on using genomics and transcriptomics to identify the origin of a tumour4-9. However, genomic testing is not always performed and lacks clinical penetration in low-resource settings. Here, to overcome these challenges, we present a deep-learning-based algorithm-Tumour Origin Assessment via Deep Learning (TOAD)-that can provide a differential diagnosis for the origin of the primary tumour using routinely acquired histology slides. We used whole-slide images oftumours with known primary origins to train a model that simultaneously identifies the tumour as primary or metastatic and predicts its site of origin. On our held-out test set oftumours with known primary origins, the model achieved a top-1 accuracy of 0.83 and a top-3 accuracy of 0.96, whereas on our external test set it achieved top-1 and top-3 accuracies of 0.80 and 0.93, respectively. We further curated a dataset of 317 cases of CUP for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 61% of cases and a top-3 agreement of 82%. TOAD can be used as an assistive tool to assign a differential diagnosis to complicated cases of metastatic tumours and CUPs and could be used in conjunction with or in lieu of ancillary tests and extensive diagnostic work-ups to reduce the occurrence of CUP.
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The site of a primary tumour has an important role in guiding the clinical care of patients with metastatic tumours and can typically be determined through the histopathological examination of tissue and through a clinical and radiological assessment of the patient. Despite improvements through sophisticated imaging modalities, specific and sensitive testing using immunohistochemistry (IHC), a concrete determination of the site of origin of the primary tumour can still be a diagnostic challenge. In fact, 1-2% of cancers are often categorized as CUPs, for which the anatomic site of primary origin cannot be assigned despite extensive diagnostic investigation and clinical correlation1,2. Patients with CUP often undergo comprehensive diagnostic work-ups including pathology, radiology, endoscopic and laboratory examinations to determine the occult primary site2,3,...