The Nature of Neuroendocrine Tumors

Matthew H. Kulke, MD: Neuroendocrine tumors are actually a very broad category of malignancies. We tend to classify them broadly in 2 big groups. One group would be pancreatic neuroendocrine tumors and the other group would be extra-pancreatic neuroendocrine tumors. Beyond that, pancreatic neuroendocrine tumors can be classified based upon the type of hormone they secrete, and they can secrete a whole range of hormones. People have heard of insulinomas, gastrinomas, etc. Then, the extra-pancreatic neuroendocrine tumors are classified, or subclassified, based on their site of origin. Common sites of origin include the lung, with bronchial neuroendocrine tumors, or, for example, small intestine neuroendocrine tumors. That is 1 big way to classify them. Then, the other important way to classify them, and something that really drives treatment, is the histology. Neuroendocrine tumors can range from very low-grade, well-differentiated tumors that tend to grow slowly to very aggressive, high-grade neuroendocrine tumors. Based on the histology, we sometimes select treatments differently.

One of the challenges does relate to the histology. There is this range of behaviors from aggressive to very indolent. Sometimes, it is a little bit tricky to decide just how you want to treat them. Another challenge can be in the treatment of low-grade well-differentiated neuroendocrine tumors. They tend to grow very slowly, which is a good thing, but at least historically it has been really challenging to identify treatments that work, especially treatments that can help shrink the tumors. That is something that has changed in recent years, and that has made the field really exciting.

Molecular testing is an interesting topic in neuroendocrine tumors. Across the board in most cancers, we tend to—almost reflexively now—get molecular testing to identify potentially-targetable mutations. In most neuroendocrine tumors, and particularly the low-grade neuroendocrine tumors, it turns out there are very few mutations. There are very few particularly in extra-pancreatic neuroendocrine tumors. In pancreatic neuroendocrine tumors there are 3 common ones: MEN1, DAXX, and ATRX. Those are all tumor-suppressor genes and therefore hard to target therapeutically. I think the answer to that question is that while we do get genomic testing and molecular testing, it does not always lead to a potential targetable mutation or potential decision that can help us with treatment. One exception to that is, in some cases, neuroendocrine tumors are associated with rare inherited genetic syndromes like MEN1. Von Hippel-Lindau disease is another one. For patients like that, you certainly do want to get germline testing, family counseling, genetic counseling, et cetera.

Not a lot is known about the microenvironment. That is an active area of research and a very important, I would say, area of research in neuroendocrine tumors right now. The aggressive neuroendocrine tumors do appear to be responsive to checkpoint inhibitors, suggesting that the environment is not particularly immunosuppressive. The big challenges right now are the low-grade neuroendocrine tumors where they seem to be very quiet genomically and potentially have an immunosuppressive microenvironment. A big question right now is can you change that, and can you potentially make these low-grade neuroendocrine tumors responsive to immunotherapy?

Transcript Edited for Clarity