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Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti–PD-L1 but not anti–CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti–PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti–IFN-γ and anti–TNF-α prevented CPI-DM in anti–PD-L1–treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

Neuroendocrine tumors comprise approximately 1-2% of all gastrointestinal tumors, and while the liver is the most common site for metastasis of these tumors, primary hepatic neuroendocrine tumors are very rare entities. Since first being reported in 1958, there have been less than 150 cases reported in the literature. Because of the infrequent occurrence of these tumors, the pool of data available for analysis regarding these tumors is small. As such, the medical community must rely on the publication of case report data to further enlarge this data pool, with the hopes of eventually having enough data to draw meaningful, statistically significant conclusions with regard to diagnosis and management of these rare tumors. We have encountered two patients at our institution within the last year with primary hepatic neuroendocrine tumors. We present their cases in this manuscript in an effort to contribute to the available data on the disease. We also provide a concise review of the literature available to date regarding primary hepatic neuroendocrine tumors.