Frequently Asked Questions - Diagnosis and Surveillance

If the carcinoid was greater than 1.5 cm diameter, or if it extended through the appendiceal wall to the serosa or the fat regardless of size, or if mesoappendix or nodes involvement were present - a right hemicolectomy should be done preceded by an OctreoScan.  If it was small and did not meet the above criteria, no colonoscopy or further workup is needed.  Carcinoid syndrome almost always requires a fairly large bulk of metastatic carcinoid and even then almost never results from appendiceal carcinoid.  There are only 2 such cases in the world literature.

This is a  contrast agent to help sonographic imaging of the portal vein and certain types of liver tumors (hepatocellular carcinoma - HCC). It does not have current immediate application in carcinoid disease since there is very limited or no experience with it in this tumor.

5-FU is a form of chemotherapy. It might shrink a carcinoid and hence lower 5-HIAA in the urine, but it also can cause a transient increase in 5-HIAA since more is released temporarily by decaying tumors. However, the drug itself does not interfere with the 5-HIAA test.

Urine 5-HIAA will correctly diagnose almost all midgut carcinoid tumors causing carcinoid syndrome but only 1/2 of foregut carcinoids causing an endocrine syndrome and almost none of the hindgut carcinoid (which rarely  cause any endocrine syndrome even when metastatic). Therefore, the combined use of other neuroendocrine  markers (blood serotonin and chromogranin A) should also be used in diagnosis and surveillace/follow-up of carcinoid.

The urine 5-HIAA test for carcinoid is crude and can be strongly influenced by special diet and drugs. The patient must be on a special diet before and during the urine collection. Even then the test can miss up to 50% of the cases. It should not be relied on alone. Other markers for carcinoid tumor are blood serotonin, tryptophan, chromogranin A, pancreatic polypeptide and, of course, the OctreoScan.

Our Medical Director, Richard R.P. Warner MD, states that ALL PPI’s (example, Nexium) will alter CgA results and
should therefore be withheld for about  1 month prior to  the chromogranin A (CgA) test.  Zantac or Tagamet can be substituted during this period.

If I understand your question correctly, you state that a diagnosis of carcinoid syndrome is suspected because of symptoms and high urine 5-HIAA, but the CT scan is normal and you want to know what other tests should now be done to prove the diagnosis. Failure to find carcinoid tumors when proven carcinoid syndrome is present is not so rare. This occurs initially in 10% of cases.

First, other findings must prove the syndrome. The various blood markers should be tested to confirm the 5-HIAA significance. This would at least include blood serotonin, chromogranin A, calcitonin, neuron specific enolase, substance P and pancreatic polypeptide; if any of these is positive it would support the diagnosis and then an OctreoScan should be done.

An OctreoScan can very occasionally show a carcinoid before CT scan or chemistries indicate its presence, but this situation is very infrequent. Visually it is used to help locate a tumor when chemistries show it is present and CT scan doesn't image it. Also when CT scan is positive the OctreoScan may show additional sites of the tumor not seen on CT.

Finally even when tumor is seen on a CT scan and chemistries are positive, the OctreoScan is useful because a positive result indicates the presence of SST2 receptors in the tumor and that means the patient will most likely respond well to treatment with Sandostatin and also has a better prognosis than does the patient with carcinoid tumor but a negative OctreoScan.

Pheochromocytoma, mast cell disease, gastrointestinal allergies, VIPoma, medullary carcinoma of the thyroid, certain rare brain tumors and also certain rare neuropsychiatric disorders, to mention a few.

An OctreoScan is fairly straightforward. While it cannot give an indication as to tumor size, it can indicate the extent of disease metastasis and show possible loci for tumors which may or may not have been suspected. Essentially what happens is this: about 4 to 24 hours prior to scanning, a Nuclear tag (about 6 milliCuries) piggybacked onto a somatostatin analog (like Sandostatin) is injected.

This tag is then taken up by any tissue exhibiting a type two receptor. Usually you find type two receptors in carcinoid cancers, liymphomas, some breast cancers and so on. The body of the person is then scanned at 24, 48 and possibly 72 hours or whenever the oncologist and radiologist deem it beneficial. The tag being tumor-specific will cause any tissue with the requisite receptors to light up on the scan film. The test is sort of go or no-go.

Most carcinoid tumors have the receptors and light up the film; about 2 percent of tumors do not have the receptors and thus do not show up. If the patient is on a somatastatin medication such as Sandostatin, the receptors will be blocked and the tumors will not show up. Sandostatin has to be stopped about 3 days prior to scanning for an accurate test to be performed.

Carcinoid syndrome requires one or more of the following for laboratory confirmation of the diagnosis: increased blood serotonin with decreased blood tryptophan, increased chromogranin A and increased urine 5HIAA or indole-3-acetic acid. In spite of the symptoms, if these criteria are not present, carcinoid syndrome is not the diagnosis.

It can be carcinoid syndrome. How high is the 5-HIAA and was the urine collected on a serotonin-free diet?  If it was more than just slightly elevated, then confirm its significance by testing blood serotonin, which should be increased; blood tryptophan, which should be decreased; and chromogranin, A which should be increased. If one or two of these are clearly abnormal, you should check the liver for metastatic tumor - by CT scan with contrast or MRI. If negative, do an OctreoScan to search for tumor foci not seen by the other imaging techniques.

I can provide some general suggestions that should be useful, as regulations restrict me from answering specific questions. Carcinoid crisis is characterized by abrupt flushing of face and sometimes upper body, usually severe fall in blood pressure and even bronchospasm with wheezing can (infrequently) occur. The attack may look like an anaphylactic attack. Diarrhea is an important part of carcinoid syndrome but is not usually simultaneous with the carcinoid crisis. It more commonly occurs as part of the anaphylactic reaction or an allergic or pseudoallergic reaction.

Standard allergy tests are not usually positive in such cases. 24 hour urine histamine, blood histamine and blood tryptase tests, particularly if obtained at the time of attack or just afterwards will establish diagnosis of allergic or pseudo allergic so called idiopathic anaphylactic attacks and mast cell disease. Epinephrine will provoke - not help - carcinoid attacks. Urine 5HIAA is helpful when positive but if depended on as the sole chemical test for carcinoid syndrome will miss 50% of cases! Better also to measure blood serotonin, tryptophan and chromogranin A.

Other blood markers associated with rare cases of severe attacks of flushing, diarrhea and fall in blood pressure are VIP, calcitonin and gastrin. They too should be measured. If any of all of the above are positive - as I expect may occur - further elaborate tests and treatment will be needed with details depending on which test(s) are positive. You should consult an expert for this if and when you arrive at this stage.

Chemical markers are important to measure and follow since they change before imaging tests do and before physical conditions (symptoms) change. They are useful early indicators of the tumor status.
The tempo of the disease varies from one patient to the next and hence the frequency with which the tests should be done may vary from yearly to every 3 months. The average is twice a year. Chromogranin A (CgA) is the most stable and dependable marker in 90% of cases. In many cases it can be supplemented by other markers which should have been tested originally and those found abnormal can also be followed subsequently.

In carcinoid, we initially include: Urine 5HIAA, Blood Serotonin, Neuron Specific Enolase, Pancreastatin, Substance P, Pancreatic Polypeptide and Atrial Naturetic Hormone (ANH) (fasting). The later (ANH) helps indicate development of carcinoid heart disease in patients with functioning tumors.In other neuroendocrine tumors, depending on type, we measure Gastrin, VIP, Calcitonin, CEA, Insulin, Glucagon, Alpha/Beta subunits of HCG and ACTH. In all cases we check CgA which is most often positive in most tumors regardless of presence or absence of any specific endocrine function.

Appropriate imaging tests such as CT scan with contrast, MRI with contrast and OctreoScan are also included in monitoring with frequency customized for each case. Included in the initial workup is also tumor-stain for Chromogranin A, Ki-67 and mitosis count.

For more information on Diagnostic and Surveillance protocols CLICK HERE.

Eugene Woltering, MD, FACS,  answers: " Well, the procedure that I use is to:
1. Look at the path report and look for key words like mitotic indices necrosis and the key word differentiation.
2. Get a Ki -67 and clearly, the lower this number the better.  Numbers over 20% ( some say 10%) are atypical indicators.
3. Get stain on the tumor for CGA and synaptophysin and ask the path guy/gal to actually count the percentage of cells that are positive/negative."

Dr. Woltering is The James D. Rives Professor of Surgery and Neurosciences, Chief of Sections of Surgical Oncology and Endocrinology, and Director of Surgical Research, LSUHSC Neuroendocrine – Carcinoid Tumors at Ochsner Medical Center -- Kenner in Louisiana. The Neuroendocrine Tumor Program at Ochsner Medical
Center – Kenner specializes in the diagnosis and management of all forms of neuroendocrine tumors
of the gastroenteropancreatic axis. In partnership with Louisiana State University Health
Sciences Center, the Neuroendocrine Tumor Program offers multidisciplinary clinical care for the neuroendocrine patient: medical, surgical and nutritional.

Octreoscan is the imaging technique of choice in addition to CT scan and MRI. In appropriate cases, Neotect Scan, FDG PET scan or F18 Dopa PET Scan and MIBG Scan in expert hands are useful. Measurement of urine and blood catecholamine could unmark a pheochromocytoma which causes flushing , fluctuating blood pressure and even diarrhea.

n general it can be stated that practically all carcinoid syndrome cases exhibit some increase in at least one of the many endocrine chemical products elaborated by the tumor and producing the syndrome. These include not only blood serotonin and urine 5HIAA but also chromogranin A, Neuron Specific Enolase, Pancreatic Polypeptide, Calcitonin, Substance P, Neurokinin A, Prostaglandin A,E and D, Histamine and Pancreastatin.

Furthermore there are a number of look alike syndromes such as Zollinger Ellison, VIPoma and Mast Cell Disease which can mimic carcinoid and be suspected by respectively measuring Gastrin, VIP, Histamine and Tryptase. Medullary Thyroid Carcinoma can cause a carcinoid-like syndrome and usually produce Calcitonin, CEA and at least one of the prostaglandins. Certain pituitary tumors make prolactin and can be associated with carcinoid like features. Prolactin is useful in this diagnosis.