A Deep Learning Framework for Classification of Neuroendocrine Neoplasm Whole Slide Images

<b>Background/Objectives</b>: Neuroendocrine neoplasms (NENs) are uncommon neoplasms. Grading informs the prognosis and treatment decision of NENs and is determined by cell proliferation, which is measured by mitotic count and Ki-67 index. These measurements present challenges for pathologists as they suffer inter- and intra-observer variability and are cumbersome to quantify. To address these challenges, we developed a machine learning pipeline for identifying tumor areas, proliferating cells, and grading NENs. <b>Methods</b>: Our study includes 385 samples of gastroenteropancreatic NENs from across British Columbia with two stains (247 H&E and 138 Ki-67 images). Labels for these cases are at the patient-level, and there are 186 patients. We systematically investigated three settings for our study: H&E, H&E with Ki-67, and pathologist-reviewed and corrected cases. <b>Results</b>: Our H&E framework achieved a three-fold balanced accuracy of 77.5% in NEN grading. The H&E with Ki-67 framework yields a performance improvement to 83.0% on grading. We provide survival and multivariate analysis with a c-index of 0.65. Grade 1 NENs misclassified by the model were reviewed by a pathologist to assess reasons. Analysis of our AI-graded NENs for the subset of pathologist-assessed G1s demonstrated a significant (<i>p</i>-value = 0.007) survival difference amongst samples the algorithm assigned to a higher grade (<i>n</i> = 20; median survival 4.22 years) compared to concordant G1 samples (<i>n</i> = 60; median survival 10.13 years). <b>Conclusions</b>: Our model identifies NEN grades with high accuracy and identified some grade 1 tumors as prognostically unique, suggesting potential improvements to standard grading. Further studies are needed to determine if this discordant group is a different clinical entity.