Jonathan R. Strosberg, MD: Simron, can you talk a little about what kinds of symptoms patients sometimes present with? And what are the unique challenges of working up patients with NETs [neuroendocrine tumors]?

Simron Singh, MD: Jon, as you know, the diagnosis of NETs is challenging. Not only is this due to the uncommon nature, but most of the symptoms are nonspecific. Most patients present with things like bloating or abdominal pain. The number of patients who present with what we are classically taught in medical school to be carcinoid syndrome—the flushing, wheezing, bronchospasm—is actually a minority. Unfortunately, we probably miss the diagnosis, as a community, quite a bit, and that leads to a delayed diagnosis. So I think something we need to work on is improving the diagnosis. Often the symptoms are just not specific enough.

Jonathan R. Strosberg, MD: Right. One thing we see quite frequently is patients with small-bowel NETs with mesenteric disease presenting with recurrent bowel obstructions year after year. Either the CT [computed tomography] scans are not done or the mesenteric masses are not recognized. You can see them in retrospect, but they’re often missed, leading to a delay in diagnosis. When it comes to working up patients, once you’ve established the pathological diagnosis of a NET, there are certain things that are unique to neuroendocrine tumors. Somatostatin receptor imaging, of course, is an example. In the past, we used to do OctreoScan. Many of them were quite crude. These days, gallium 68 DOTATATE [Netspot] has really improved the sensitivity and the resolution ability to detect small lesions. It often has the ability to detect a primary site. So the gallium 68 DOTATATE scan has really become an important part of the initial patient work-up.

And then, of course, it is important to recognize hormonal syndromes and order the appropriate hormonal tests. For example, in patients with diarrhea and flushing, you should obtain a urine 5-HIAA [5-hydroxyindoleacetic acid], or serum serotonin, or even a blood 5-HIAA. Patients with pancreatic neuroendocrine tumors can present with symptoms such as heartburn, diarrhea, hypoglycemia, and weight loss. Recognizing the important hormonal syndrome is an important part of the work-up. There’s a lot of controversy about nonspecific tumor markers like chromogranin. What are your thoughts on that?

Simron Singh, MD: I think chromogranin A is probably the best biomarker that we have right now. I do think we need to realize that there are a lot of reasons for false elevation of chromogranin A—things like proton pump inhibitor use, hypertension, a lot of other medications, and even diet. So I think we have to be very cautious about using chromogranin A as a diagnostic tool. I think it can cause a lot of anxiety, not only for clinicians but for patients as well.

One thing I do want to mention is the importance of pathology and having a good pathological impact, in terms of when we do diagnose a NET. There are a lot of features on the pathology. When you see a pathology report, what are those key features that you look for to make a neuroendocrine diagnosis and to start planning treatment? What do you look for?

Jonathan R. Strosberg, MD: These days, a pathology report that says simply neuroendocrine tumor or carcinoid tumor is inadequate.

Simron Singh, MD: Agreed.

Jonathan R. Strosberg, MD: Mitotic rate and Ki 67 should be measured in all patients, leading to tumor grade that is low, intermediate, and high. And ideally, especially with the high-grade tumors, you would want the pathologist to also comment on differentiation. We realize that not all high-grade tumors are poorly differentiated. So I ask the pathologist to independently evaluate the tumor grade, typically measured at the hot spot, and to also comment on the tumor differentiation. Those things usually correlate with each other, but not always.

Simron Singh, MD: This new phenomenon or this new description of a well-differentiated G3 neuroendocrine tumor is very important. As you said, it’s important that we understand both the Ki 67 and mitotic count but also the differentiation. How about for immunohistochemistry? Is there anything that you specifically look for when you’re making that diagnosis?

Jonathan R. Strosberg, MD: Well, chromogranin is a standard neuroendocrine tumor feature. There are certain additional stains, such as CDX2 and Islet-1, that can be done to help identify a primary site in cases of an occult primary tumor. With our modern radiologic techniques, we can usually identify the primary. If there’s a mesenteric mass in a typical patient with carcinoid syndrome, you can pretty much assume that the primary is in the small intestine. But occasionally those additional stains can be helpful.

Simron Singh, MD: How about TTF-1 [thyroid transcription factor 1]? Do you find that useful?

Jonathan R. Strosberg, MD: TTF-1 is positive in about 50% of lung NETs. It’s not specific and is not that sensitive, but I suppose it can be helpful in some cases.

Transcript Edited for Clarity