Neuroendocrine Tumor Symptoms and Delayed Diagnosis

Neuroendocrine tumors, often shortened to NETs, start in cells of the diffuse neuroendocrine system. Those cells sit scattered through the gut, the lungs and other organs. They sense what is happening around them and release hormones in response.

Two facts explain most of the delay in diagnosis. NCI puts the worldwide age-adjusted incidence at about 2 per 100,000 people. NETs make up roughly 0.5 percent of all newly diagnosed cancers. The average age at diagnosis is 61.4 years.

So a doctor may see very few in a career. And the tumors are usually slow-growing. A slow tumor produces slow symptoms. Slow symptoms get explained away.

Most people have heard of flushing and diarrhea in connection with these tumors. That cluster is called carcinoid syndrome. NCI states it occurs in fewer than 20 percent of patients with neuroendocrine tumors.

It happens when the tumor releases vasoactive amines, a group of chemical messengers, into the bloodstream faster than the body can break them down. The main features are:

• Flushing, meaning sudden redness and heat in the face and upper body.
• Abdominal pain and diarrhea.
• Bronchoconstriction, meaning narrowing of the airways with wheeze.
• Carcinoid heart disease.

There is a crucial detail about timing. The liver breaks these chemicals down efficiently. So carcinoid syndrome rarely appears until the tumor has spread to the liver. By the time the classic syndrome shows up, the disease has usually moved.

There are exceptions, and they matter. The syndrome can appear without liver spread when a tumor's venous blood bypasses the liver. NCI names primary lung or ovarian carcinoids, small bowel tumors involving the pelvis or the space behind the abdomen, and extensive bone spread.

This complication is under-recognized. NCI reports that carcinoid heart disease develops in more than one-third of patients with carcinoid syndrome.

The mechanism is fibrosis. The heart valves thicken and stiffen. The tricuspid and pulmonic valves, on the right side of the heart, are affected more than the mitral and aortic valves on the left. The results NCI lists are tricuspid and pulmonic regurgitation, pulmonary stenosis, mitral and aortic insufficiency, and heart rhythm problems.

Severe carcinoid heart disease is associated with reduced survival. If carcinoid syndrome is confirmed, ask whether an echocardiogram has been done and how often it will be repeated.

Most NETs do not cause carcinoid syndrome. What they cause depends on where they are and what they block or bleed.

Vague, ongoing abdominal symptoms are common. Cramping pain that comes and goes, unexplained diarrhea, and periodic bloating are the usual complaints. These overlap almost exactly with irritable bowel syndrome, which is far more common. That overlap is the single biggest reason for a delay.

Two patterns deserve a second look:

• Symptoms attributed to irritable bowel syndrome that keep worsening, or that start after age 50.
• Flushing that is not clearly linked to heat, alcohol, spicy food or menopause, especially if it comes with diarrhea.

Neither proves anything. Both are worth naming out loud rather than absorbing. Our page on cancer symptoms covers how to describe a pattern so it is taken seriously.

If a NET is suspected, two biochemical tests come up. Both have known weaknesses, and knowing them changes how you read a result.

The first is a 24-hour urine collection for 5-hydroxyindoleacetic acid, shortened to 5-HIAA. It is a breakdown product of serotonin. NCI puts its specificity at approximately 88 percent, but reports sensitivity as low as 35 percent. A specificity of 88 percent means a positive result usually means something. A sensitivity of 35 percent means a normal result misses a great many tumors.

The test also has practical demands. It takes 24 hours, and it requires avoiding serotonin-rich foods beforehand. NCI names bananas, tomatoes and eggplant.

The second is plasma chromogranin A, or CgA. NCI describes plasma CgA levels as very sensitive markers, but nonspecific. They also rise in other neuroendocrine tumors, including pancreatic tumors and small cell lung cancer. NCI states that plasma CgA appears to be a better marker than urinary 5-HIAA, and that levels track with how extensive the disease is.

One false-positive cause is worth knowing before your blood is drawn. Proton pump inhibitors, the common acid-reducing drugs, raise CgA. NCI notes this happens even with short-term, low-dose treatment. Tell whoever orders the test if you take one.

More than 70 percent of neuroendocrine tumors of the gut and pancreas carry somatostatin receptors on their surface. There are five subtypes, and subtypes 2 and 5 predominate.

That biology makes a specific kind of scan possible. A radioactive tracer built to bind somatostatin receptors will light up the tumor wherever it is. NCI describes somatostatin receptor scintigraphy using indium In 111-labeled octreotide. It finds small primary tumors and spread more readily than conventional imaging, in a single session.

Other imaging NCI lists includes bone scintigraphy with technetium Tc 99m-MDP, iodine I 123-MIBG scintigraphy, CT, capsule endoscopy, enteroscopy and angiography.

The practical question is direct. If a NET is suspected and a standard CT is normal, ask whether somatostatin receptor imaging is indicated.

NCI's prognostic factors are the site of origin, the size of the primary tumor, and how far the disease extends.

Site matters more than people expect. NCI states that patients with neuroendocrine tumors of the appendix and rectum generally survive longer than those with tumors of the stomach, small intestine or colon. Tumors in the small intestine are more likely to spread than those in the appendix, colon or rectum, even when they are small.

Two markers on the pathology report carry weight. High expression of Ki-67, a protein that marks dividing cells, and of the p53 tumor suppressor protein, have been linked to worse outcomes. NCI notes some researchers argue the Ki-67 index is most useful for stomach lesions specifically.

NCI also lists three adverse clinical indicators: carcinoid syndrome, carcinoid heart disease, and high levels of urinary 5-HIAA or plasma chromogranin A.

• Which specific site did my tumor start in, and what size was it?
• What is the Ki-67 index on my pathology report?
• Has somatostatin receptor imaging been done, and if not, why not?
• Was my chromogranin A drawn while I was taking a proton pump inhibitor?
• If I have carcinoid syndrome, when is my echocardiogram, and who repeats it?
• Is there a neuroendocrine tumor center where my case could be reviewed?

That last question is worth pressing. These tumors are uncommon enough that experience varies a great deal between centers. Our page on getting a second opinion covers how to arrange one, and metastatic cancer explains what spread does and does not mean.

• NCI PDQ on GI neuroendocrine tumors, for doctors
• NCI PDQ on GI neuroendocrine tumors, for patients