**2. Conclusions**

A significant and growing body of evidence points to a critical role in the activation of inflammation and the immune response in the pathogenesis of ACP. Multiple studies have demonstrated high levels of inflammatory markers and cytokines in both ACP cyst fluid and solid tumor. Many of these employed advanced genomic, proteomic and transcriptomic techniques to demonstrate expression of multiple genes involved in the inflammatory and immune response in these tumors. A number of these markers represent attractive potential targets for directed therapy in the treatment of ACP. Specifically, due to existing experience combined with proven efficacy in other cancers and diseases, IL-6 and the immune checkpoint inhibitors (anti-PD-1/PD-L1 and anti-CTLA-4) may represent particularly good targets/therapies. Similarly, combinations of such agents have proven very effective in prolonging survival in malignant cancer such as melanoma, renal cell carcinoma and non-small-cell lung cancer that were failing more traditional treatment. Such combination therapy may also present a potential therapeutic strategy in the management of recurrent and treatment-resistant ACP. In addition, these agents might also be combined with agents that do not specifically interact with inflammatory/immune processes (e.g., MEK inhibition). In fact, Apps et al. [10] demonstrated that MAPK/ERK pathway likely plays a pivotal role in the pathogenesis of both murine and human ACP. In addition, they showed that treating human ACP with trametinib ex vivo resulted in decreased proliferation and increased apoptosis. Finally, recent work has also demonstrated the pivotal role played by senescence and the SASP in the pathogenesis of these tumors. It is possible that the strong SASP signature drives much of the inflammation seen in ACP, and that targeting SASP associated pathways may provide an effective treatment strategy in the future. Due to the benign histological nature of the disease, it is likely that initial clinical trials of such agents will be reserved for patients with recurrent or progressive disease. In addition, due to the rarity of the disease and the scarcity of tumor tissue it is vital that pediatric centers continue to work together to share knowledge and tissue in an effort to accelerate the development of safe and efficacious treatments. Such efforts will hopefully result in improved outcomes for children suffering from this chronic and often devastating disease. Finally, other advanced techniques are being developed that continue to enhance our ability to better diagnose, and identify biomarkers in oncologic diseases that may result in the development of better therapeutics [57,58]. It is possible that such techniques if applied to ACPs could result in significant advances in the diagnosis and treatment of ACP in the future.

**Author Contributions:** R.W. as the first author was primarily responsible for drafting the article manuscript. E.P. also helped draft the manuscript and helped with editing the final submission. A.G. provided the pathology figures and the descriptions of the same. T.H. acted as the lead author and guided the direction of the manuscript as well as being the primary editor of the final submission. All authors have read and agreed to the published version of the manuscript.

**Funding:** No external funding was received for the production of this research.

**Conflicts of Interest:** The authors declare no conflict of interest.
