The Carcinoid Cancer Foundation is pleased to announce that Jerome S. Zacks, MD, cardiologist, is the featured NET expert for CCF’s Ask the NET Expert program during May 2022. Launched in February, the Ask the NET Expert is a web-based program* for the neuroendocrine tumor community featuring a different NET expert each month who will answer your questions.
A cardiologist, Dr. Zacks has extensive experience caring for patients with carcinoid heart disease. He is the founder and Medical Director of the Carcinoid Heart Center, located in New York City. The Center’s patient focus is two-fold: first, on issues related to carcinoid syndrome and its resultant carcinoid heart disease. Second, based on the belief that a healthy heart is important when living with neuroendocrine cancer and all its manifestations and complications, the Carcinoid Heart Center focuses on all the important cardiovascular risk factors, including hypertension, diabetes, lipid disorders, obesity, smoking behavior, homocysteine, cardio-selective C-reactive protein, dietary factors and life-style/exercise habits. Dr. Zacks is also Associate Clinical Professor of Medicine, Cardiology, at the Icahn School of Medicine at Mount Sinai in New York City.
Dr. Zacks is a co-author of “Diagnosing and Managing Carcinoid Heart Disease in Patients with Neuroendocrine Tumors: An Expert Statement,” published in the Journal of the American College of Cardiology. Given that up to 50 percent of neuroendocrine cancer (carcinoid) patients go on to develop carcinoid heart disease, which is often more life-threatening for patients than the usually slow-growing neuroendocrine tumors, these guidelines are a huge step towards the goal of educating patients and doctors about the current gold standard in diagnosis and treatment.
QUESTIONS AND ANSWERS
QUESTION: How is carcinoid heart disease diagnosed?
ANSWER: The most sensitive and specific test for carcinoid heart disease is the echocardiogram; it is deemed 100% sensitive and specific for the valvular changes characteristic of carcinoid heart disease. The changes include valvular thickening, retraction and, often, stenosis and insufficiency (leaking of the valve).
QUESTION: For someone who becomes extremely unstable and goes into carcinoid crisis in procedures, would you suggest the octreotide protocol for a right heart catheterization? What precautions should be taken if any?
ANSWER: To help prevent a Carcinoid Crisis during a cardiac catheterization, the effects of serotonin, especially flushing and diarrhea, can often be prevented or ameliorated with an IV octreotide drip at a continuous dose of 100-200 mcg/hr during the procedure. in addition, an IV dose of Solucortef 100mg can often prevent the marked hypotension (low blood pressure) caused by tumor secretion of bradykinin. The IV octreotide drip can be increased by 100 mcg/hr increments, and IV Solucortef 100mg can be repeated during the procedure if signs and symptoms of a Carcinoid Crisis persist or recur. In addition, for hypotension, copious IV fluids should be administered to counteract the marked venous relaxation and dilation caused by bradykinin. If hypotension persists, IV vasopressin should be given to help restore blood pressure.
QUESTION: I was diagnosed with lung nets 4 years ago and have been taking octreotide shots for 4 years and Xermelo to control my carcinoid syndrome. I often get chest pain mimicking a heart attack. I was told it is the cancer causing my arteries to spasm. Can you explain this to me? I do take nitro glycerin to get relief.
ANSWER: The octreotide given to patients with a neuroendocrine tumor is for the purpose of suppressing tumor release of vasoactive amines, substances which can produce symptoms such as flushing, diarrhea, abdominal pain and others. The Xermelo (telotristat ethyl) blocks tryptophan hydroxylase, the enzyme involved in the first step in the tumor production of serotonin, the cause of diarrhea and carcinoid heart disease. Although chest pain has been known to result from tumor release of substances known to cause coronary artery spasm, it is a rare occurrence. Therefore, other causes of chest pain should be entertained and excluded before concluding that vasospasm is the sole cause of chest pain. A simple test for the exclusion of coronary artery disease is the CT coronary angiogram with a coronary calcium scoring. This involves the use of a CAT scan for the purpose of documenting coronary artery calcium and a second imaging after a peripheral venous injection of a clear liquid “dye” which appears white in the coronary arteries on CT scan imaging. Other possible causes of chest pain mimicking coronary heart disease include GERD (gastroesophageal reflux disease), the upward leaking of stomach acid into the esophagus at its junction with the stomach, and esophageal spasm which occurs when the normal peristalsis movement of the esophagus is interrupted by spasm of the esophagus, often triggered by swallowing certain foods. So, not all chest pain is caused by coronary spasm; other causes must be excluded. Nitroglycerine is often helpful if the diagnosis is truly coronary vasospasm.
QUESTION: I have carcinoid heart disease, surgery, 2 new valves. High blood pressure even with blood pressure medicine. When I go into carcinoid syndrome my blood pressure is sort of normal. Otherwise It’s always high. Yesterday morning I woke up to 201/123. Is this normal?
ANSWER: First, concerning hypertension: It’s important to maintain a normal blood pressure (120/80 or less). And if one observes a reduction of blood pressure during a carcinoid crisis, it implies the secretion of one or more vasoactive substances which cause dilation of blood vessels, especially bradykinin, a potent vasodilator. A blood pressure of 201/123 is very high and of concern; it merits a rapid treatment to reduce the pressure to a normal level. Second, concerning carcinoid heart disease, especially in patients with bioprosthetic (tissue) valves: It’s important to monitor one’s serotonin level closely since this substance, secreted by the carcinoid tumor, is considered to be the prime cause of the valve thickening, narrowing and leaking (serotonin released by the tumor stimulates serotonin receptors on the inner surface of the right heart, in turn stimulating fibroblast proliferation – scarring – especially involving the two right heart valves – tricuspid and pulmonic). In someone who has already had valves replaced with tissue valves, if serotonin remains elevated there is a high risk of recurrence of the carcinoid valve abnormalities. Fortunately, on February 28, 2017, the U.S. Food and Drug Administration approved Xermelo (telotristat ethyl) tablets in combination with somatostatin analog (SSA) therapy for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled. Although there is not a randomized controlled study proving that this drug will prevent carcinoid heart disease, the strong association of serotonin and mortality in patients with the carcinoid syndrome, and the proven efficacy of telotristat in blocking serotonin production by the tumor, strongly suggests it’s justified to treat carcinoid syndrome patients, who are post-op valve replacement with tissue valves, with this drug if their serotonin level is above normal.
QUESTION: I have had very high levels of Chromogranin A consistently for at least two years and don’t take proton pump inhibitors. Two Gallium-68 scans did not detect any neuroendocrine tumors. Can an elevated Chromogranin A level occur in healthy people and how would a neuroendocrine tumor be diagnosed if nothing shows on a Gallium-68 scan?
ANSWER: Although chromogranin A is considered a neuroendocrine tumor (NET) marker, there are many instances of non-NET patients having an elevated chromogranin A; PPI medication is not the sole cause. For a non-NET patient with an elevated chromogranin A, a prudent approach would be to search for a neuroendocrine tumor; if none is found, then perhaps re-testing the blood test 6 months later might be prudent. And it would be appropriate to select the pancreastatin level (the breakdown product of chromogranin A which is more sensitive and specific for a NET) instead of chromogranin A which can be influenced by PPI’s and other factors. The reason for a repeat exam in 6 months is the possibility of a tiny NET, which did not show up on prior imaging, to manifest itself after a period of further growth.
QUESTION: I have had several PET scans, all lighted up in pancreas. I am allergic to CT contrast. I have had an inconclusive result on the biopsy of the pancreas. Chromogranin A very high. Yes, I have flushing, diarrhea and pain. Should I go for exploratory surgery?
ANSWER: This case illustrates the benefits of NET patients to be seen in consultation at a NET center. Concerning a persistent hot spot, on a PET scan, in the pancreatic head, this is a common finding in patients who have no other finding consistent with a NET. It merits periodic follow-up. Concerning an allergy to CT contrast media, the radiologists’ experience with the prevention of dye reactions is very important in such an instance. Concerning equivocal biopsy results, this merits the opinion of a NET tumor board which is a routine service provided by NET centers. For example, at our institution (Mt Sinai in NY City), the NET tumor board meets weekly to discuss all NET cases requiring multi-specialty decisions on diagnosis and treatment. Concerning chromogranin A, a more sensitive and specific marker is pancreastatin, the break-down product of chromogranin A which is unaffected by PPI medications and many other factors. Concerning symptoms of a possible carcinoid syndrome, other biomarkers including serotonin and others, can be tested to help confirm the presence or absence of a NET. (A NET specialist will be familiar with these tumor- secreted vasoactive amines). Concerning a decision for or against surgery, a NET tumor board would be most helpful regarding a decision for or against surgery to confirm the presence or absence of a NET tumor.
QUESTION: For a functioning bronchial neuroendocrine tumor is Carcinoid Heart Disease found specifically in the valves? Or is a finding of concentric left ventricular hypertrophy on an echocardiogram concerning for Carcinoid Heart Disease as well?
ANSWER: In the instance of a functioning bronchial neuroendocrine tumor, carcinoid heart disease typically would involve the left heart valves (aortic and mitral valves) because serotonin from the pulmonary veins drains directly into the left heart; ultimately, that serotonin will be deactivated by the liver before reaching the right heart. Concentric left ventricular hypertrophy is a hallmark of hypertensive heart disease and usually is not directly associated with carcinoid heart disease, a disease usually caused by serotonin excess.
QUESTION: Is it possible for carcinoid tumors to invade or metastasize to the thyroid?
ANSWER: A carcinoid metastasis to the thyroid can occur but is rare and must be differentiated from a primary thyroid NET (medullary carcinoma of the thyroid). The latter is seen in 100% of patients with the genetic disease, Multiple Endocrine Neoplasia type 2 (MEN-2).
QUESTION: is every neuroendocrine tumor a carcinoid? Can neuroendocrine tumors cause weight loss? How do I know if a tumor is functional or non- functional?
ANSWER: “Carcinoid tumors, which are one subset of tumors called neuroendocrine tumors, usually begin in the digestive tract (stomach, appendix, small intestine, colon, rectum) or in the lungs.” Neuroendocrine tumors can definitely cause weight loss, especially those which cause partial bowel obstruction, diarrhea or recurring or persistent pain. NETs which secrete substances which cause symptoms (especially vasoactive amines) are termed “functional tumors”; those which fail to secrete symptom-causing substances are termed “nonfunctional tumors”; they create symptoms when their growth results in tumor compression or obstruction of body organs or other structures.
QUESTION: How often should a person diagnosed with carcinoid, with no history of heart disease, see a cardiologist? What tests should be done routinely?
ANSWER: This is a very pertinent question. A person diagnosed with a carcinoid malignancy, but no evidence on an echocardiogram of carcinoid heart disease, merits blood tests for neuroendocrine tumor (NET) markers (perhaps most important would be a pancreastatin level and serotonin level). In addition, a baseline echocardiogram should be performed for every NET patient…not only to determine the presence or absence of carcinoid valve disease, but also for evidence of any non-carcinoid abnormality. It would be ideal for patients with carcinoid tumors, but no evidence of carcinoid heart disease, to see a cardiologist annually; a decision can then be made as to whether an annual echocardiogram is warranted. This would provide the added benefit of enabling a careful check for the presence or absence of cardiovascular risk factors.
QUESTION: How would carcinoid heart disease present in lung primary NET? High kallikrein, high CgA, high cortisol- how is carcinoid heart disease different from age-related aortic and mitral valve leaking?
ANSWER: These are excellent questions , , ,
Carcinoid heart disease in a patient with the carcinoid syndrome, including excess production of serotonin due to a bronchial carcinoid, might affect the left heart valves (aortic and mitral valves); this is different from the valves typically affected by carcinoid syndrome patients with liver metastases producing a high concentration of serotonin in the inferior vena cava. In the latter situation, the right heart valves (tricuspid and pulmonic valves) are typically affected by the serotonin carried in platelets in the blood traveling from the liver through the right heart, then into the lungs where serotonin is inactivated before it travel on to the left heart valves.
The high kallikrein is responsible for the release of vasoactive substances, including kinins; bradykinin, a potent vasodilator which causes a marked reduction of blood pressure, can be a major contributor to a “carcinoid crisis”, marked by extreme diarrhea, flushing and shock.
High chromogranin A (CgA) is often noted in neuroendocrine tumors; however, false elevations of CGA can be noted in persons on PPI (proton pump inhibitor) anti-acid medications. A better NET biomarker is the breakdown product of chromogranin A, pancreastatin, which is unaffected by PPI medications.
A high cortisol can be the result of an adrenal gland or pituitary gland tumor, or the result of ectopic production of adrenocorticotropic hormone (ACTH).
Carcinoid valve disease is predominantly caused by serotonin stimulation of carcinoid receptors on the inner lining of the heart, including the valve leaflets. When stimulated by serotonin and other substances, the receptors stimulate fibroblast proliferation (scarring), resulting in thickening and distortion of the affected valve leaflets as well as leaking of the valves. This characteristic damage caused by high serotonin levels is different from age-related degeneration with resultant thinning and leaking of the aortic and mitral valves. Aging can also cause progressive calcification of the aortic valve as well as the mitral valve annulus. However, the aging effect does not cause the thickening and retraction of leaflets characteristic of carcinoid’s serotonin effects.
QUESTION: What causes heart issues for us patients with small intestine NETs with metastases stage IV?
ANSWER: The carcinoid right heart disease typically results from the high concentration of serotonin secreted from the metastases in the liver; the serotonin is carried via the inferior vena cava directly to the right atrium and from there to the tricuspid and pulmonic valves. The small bowel carcinoid tumors can secrete serotonin locally, causing scarring and obstruction of the intestine; the tumor can also spread regionally via lymphatics to adjacent lymph nodes where the secretion of serotonin causes fibrosis (scarring), and the tumor can spread via the blood vessels to the liver.
QUESTION: What are the symptoms of carcinoid heart disease?
ANSWER: Typical symptoms of carcinoid heart disease are those of right heart valve disease, including right heart failure (fatigue, edema of legs, ascites (abdominal fluid) and pleural effusion (fluid around the lungs); shortness of breath can occur if there is pleural effusion. Symptoms of left heart failure, including shortness of breath, can occur in patients with left heart valve involvement with carcinoid heart disease.
QUESTION: Is everolimus 0.5 mgs (used in transplant patients) the same substance as everolimus 5 mgs or 10 mgs (used in NETs)?
ANSWER: Everolimus, an mTOR pathway inhibitor, is used as an immunosuppressive medication in transplant patients as well as a targeted anti-tumor medication in NET patients. In the above question, the 0.5mg dose is much lower than the 5-10mg dose used for NET treatment.
QUESTION: When having surgery to remove a small carcinoid tumor from the lung how high is the incident of excess hormones being released into the system?
ANSWER: The finding of high vasoactive substances and/or hormones in the blood of a lung NET patient can be used as useful biomarkers for following the patient after surgery or other tumor-reductive procedures. There is a small risk of tumor secretion of vasoactive substances, causing a carcinoid crisis, during surgery. Generally, the administration of IV octreotide, IV corticosteroid, and copious IV fluids will prevent or control a carcinoid crisis during surgery.
QUESTION: Is metastatic neuroendocrine heart disease treatable and is it rare? Also, is metastatic neuroendocrine ovarian cancer treatable?
ANSWER: Metastasis to the heart occurs in approximately 5% of patients with carcinoid syndrome. Usually, heart metastases, if not affecting heart function, are monitored with serial imaging (cardiac MR, echocardiograms and nuclear imaging). However, if there is the threat of embolization through a heart valve, the metastatic tumor should be removed with surgery.
Metastatic ovarian NETs can cause carcinoid heart disease (without liver metastasis) because vasoactive substances, including serotonin, travel from the ovaries directly into the inferior vena cava, thereby bypassing the liver and draining into the right atrium. Patients with an ovarian NET are optimally treated by a team, including a gynecologic oncologist, a NET specialist, a radiologist, and often, a cardiologist and surgical oncologist.
QUESTION: I have consulted a naturopath doctor with solid credentials. She has recommended several supplements and Keto Diet to recovering my energy. My specialist recommended I build myself up after tumors in my liver grew while on everolimus. Is this a good way to gain back energy?
ANSWER: Naturopathic care might involve helpful measures, in terms of nutritional and healthy lifestyle measures. However, it’s not a substitute for care directed at the diagnosis and management of specific medical illnesses, including neuroendocrine tumors. The standard of care for persons with neuroendocrine tumors with liver metastases is team care with a neuroendocrine tumor (NET) expert leading the team and the presentation of the patient’s data (history, treatment and test results) to a tumor board which meets regularly to discuss the best treatment of each patient whose data are presented. If one has a NET, it’s optimal to seek the opinion of a NET expert.
QUESTION: Can you get plaque lesions on the left side of heart?
ANSWER: Plaque formation can be found on left heart valves in carcinoid syndrome patients with liver metastases and a patent foramen ovale or extremely high serotonin levels, or patients with carcinoid syndrome due to a bronchial carcinoid tumor.
*The opinions expressed by NET experts, as well as the questions posed, haven’t been created or suggested by the Carcinoid Cancer Foundation, and CCF doesn’t endorse or promote any of the views or information expressed by the NET experts. You should not rely on the opinions expressed by the NET experts but should seek guidance and direction from your own medical advisors regarding any choices you make regarding your health and treatments.
