Self-supervised learning in non-small cell lung cancer discovers novel morphological clusters linked to patient outcome and molecular phenotypes

Histopathological images provide the definitive source of cancer diagnosis, containing information used by pathologists to identify and subclassify malignant disease, and to guide therapeutic choices. These images contain vast amounts of information, much of which is currently unavailable to human interpretation. Supervised deep learning approaches have been powerful for classification tasks, but they are inherently limited by the cost and quality of annotations. Therefore, we developed Histomorphological Phenotype Learning, an unsupervised methodology, which requires no annotations and operates via the self-discovery of discriminatory image features in small image tiles. Tiles are grouped into morphologically similar clusters which appear to represent recurrent modes of tumor growth emerging under natural selection. These clusters have distinct features which can be identified using orthogonal methods. Applied to lung cancer tissues, we show that they align closely with patient outcomes, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype.