Why Neuroendocrine Tumors Are So Hard to Find and How Somatostatin Receptors Open Up New Possibilities

Overview

“Of all the frustrations that come with a neuroendocrine tumor (NET) diagnosis, the most common one I hear from patients and their families is this: it took too long to get here,” says Dr. Eliot Siegel, MD, FACR, FSIIM, DABR. Dr. Siegel is a Founding Physician of United Theranostics, and a nuclear oncologist who has developed something of a specialty in treating these notoriously difficult-to-diagnose tumors. In describing the frustrations associated with NETs, he recounts how patients often describe years of vague symptoms, multiple specialists, tests that came back normal, and then, finally a diagnosis, often at a stage when the disease has already spread beyond its original location. The delay, he clarifies, is not a failure of the patients or even of their physicians. It is a reflection of how genuinely difficult NETs are to find using conventional approaches. Understanding why requires some background on the biology of these tumors, as well as the imaging technology that was developed to overcome this difficulty.

Why the Diagnosis Takes So Long

Neuroendocrine tumors are notorious masters of disguise. Because these tumors arise from hormone-secreting cells and can themselves secrete hormones, the symptoms they produce (flushing, diarrhea, abdominal pain, fatigue) closely mimic a long list of far more common conditions. A patient might be told for years that they have irritable bowel syndrome, menopause, anxiety, or a functional gastrointestinal disorder. “By the time the word neuroendocrine is finally spoken,” Dr. Siegel relates, “many patients have already spent years searching for an answer, and the disease has often metastasized from its original site in the gut, pancreas, or lungs.”

For referring physicians, there is an additional complication: conventional imaging often simply misses these tumors. Standard CT scans and MRIs look at anatomy. They describe the size and shape of tissues and organs. Early-stage NETs can be only a few millimeters in diameter, though, and may look indistinguishable from normal surrounding tissue. In these cases, the scan can be read as negative for disease. The patient is sent home. The disease continues to grow.

The turning point in most neuroendocrine tumor diagnosis journeys is when a physician suspects a neuroendocrine origin and orders a different kind of imaging. Typically, this suspicion arises because of elevated hormone markers in blood or urine, or a pathology finding from a biopsy. Rather than ordering additional anatomy-based imaging, they request molecular imaging: a scan that helps to identify cell surface proteins expressed by the tumor cells.

The Biology That Makes This Possible: Somatostatin Receptors

To understand why molecular imaging works for NETs, it helps to understand what makes neuroendocrine tumors biologically distinctive.

“Imagine the surface of a tumor cell as a locked door,” explains Dr. Siegel, “and on that door are thousands of tiny keyholes. In biology, these keyholes are called ‘receptors,’ and they are protein structures that are designed to receive specific signaling molecules that tell the cell what to do.” In a healthy body, a hormone called somatostatin is one of these “keys.” “It signals the somatostatin receptor, usually telling it to make the cell stop growing or to stop releasing hormones.”

What makes the cells of neuroendocrine tumors distinctive is that they typically express somatostatin receptors (SSTRs) at far higher levels than normal tissue. As Dr. Siegel describes it: “When they’ve built an unusually high number of these specific keyholes on their surface…we call this ‘overexpression,’ and it’s our greatest advantage in fighting neuroendocrine tumors.” Whereas a healthy cell might have a modest number of these receptors (or keyholes) on its surface, a NET cell may carry thousands. That overexpression is a defining feature of the disease and makes it identifiable via molecular imaging. To find the tumor, scientists design synthetic versions of the somatostatin “key” attached to a safe radiotracer. When introduced to the body, these synthetic keys seek out and lock into the thousands of overexpressed keyholes, acting like a tracking beacon that allows a PET scan to clearly illuminate the hidden tumor.

SSTR Subtypes: Not All Keyholes Are Created Equal

There isn’t just one type of somatostatin receptor, though. “A neuroendocrine tumor might actually express a combination of the subtypes, but Subtype 2 is by far the most commonly overexpressed,” elaborates Dr. Siegel. He goes on to explain how there are five distinct subtypes, as illustrated by the chart below.

The difference in expression rates has tremendous implications for treatment options. “Because SSTR2 is so dominant, the vast majority of the therapies we use in the clinic today are engineered specifically to act as the perfect key for the SSTR2 keyhole,” elaborates Dr. Siegel. Additional existing and future treatments target multiple subtypes.

Can a Tumor’s Receptor Expression Change Over Time?

Dr. Siegel was careful to note that a tumor’s receptor expression can change. “A tumor’s biology is dynamic, not static,” he says, “and over months or years, a tumor may stop expressing somatostatin receptors.” While modern treatment methodologies are evolving in the hopes of lowering the likelihood that this occurs, sometimes treating the cancer can leave room for treatment-resistant cells to continue growing. “It’s a critical pivot point that tells the clinical team that the cancer has likely become more aggressive,” he continues, “and that at this stage, we need to shift our strategy away from SSTR-targeted therapies and look toward other options, like systemic chemotherapy or different targeted agents.”

Altering the Course of NET Treatment

We’ve come a long way since the underlying biology of somatostatin was first discovered in 1973. In the decades that followed, endocrinologists learned to influence the growth and hormone release of neuroendocrine cells. Scientists went on to characterize the somatostatin receptor family. And by the 2000s, oncologists could reliably find NETs that would have been invisible a generation earlier. “Today, we’re still working towards developing more precise ways of targeting these cells and treating them,” remarks Dr. Siegel, “and somatostatin receptors are playing a crucial role in this fight.”

If you are navigating a diagnostic journey or have questions about molecular imaging options, o discuss your specific situation.

If you are navigating a diagnostic journey or have questions about molecular imaging options, our team of nuclear medicine physicians is available to discuss your specific situation and coordinate a personalized consultation at one of our Nuclear Oncology Centers of Excellence.