Carcinoid Tumors

Relatively new to medical recognition, carcinoid tumors were first identified as a tumor type in the mid 1800’s and were not called carcinoid until the early 1900’s.  The term carcinoid was used to identify the tumors as between malignant carcinomas and benign adenomas.  Carcinoids belong to a group of growths called neuroendocrine (NE) tumors.  Each type of neuroendocrine tumor may produce a different primary hormone and an accompanying different syndrome; i.e., the carcinoid causes different symptoms.

Why is this important for us to include in a discussion of carcinoid? First, each of these syndromes, though having different features, can include flushing and/or diarrhea and may be confused with Carcinoid Syndrome (discussed later).  Secondly, a carcinoid can occasionally have a mixed function causing another syndrome along with Carcinoid Syndrome.  This is the result of carcinoids producing one or more of these other hormones along with production of its own specific hormone(s).  Thirdly, inherited familial (genetic) conditions can cause the development in an individual of several different types of neuroendocrine tumors (and their respective syndromes).  This can include carcinoid along with other types of NE tumors. 

Carcinoids arise from enterochromaffin cells (glandular endocrine-hormone producing cells), which are widely distributed in the body.  The cells are found in greatest amounts in the small intestine and then in decreasing amounts in the appendix, rectum, lung, pancreas and, although rarely, may also be found in ovaries, testes, liver and bile ducts. These cells have features that make them identifiable under the microscope when stained with silver containing chemicals. Special stains for the particular hormones that enterochromaffin cells can make identify the hormone substances in carcinoid tumor cells and thereby confirm the diagnosis of the microscopic exam on carcinoid tumor samples taken at biopsy.

Large studies of many individuals indicate that insignificant small carcinoid tumors occur fairly commonly (perhaps 1/100 people) and may last a lifetime, causing no problems and do not spread is fairly common.  As noted above with enterochromaffin cells having the highest frequency in the small intestine, carcinoid tumors are found most commonly in the small intestine.   Small intestine tumors are rare (1% of all GI cancers), however, carcinoids of clinical importance comprise about 50% of all small intestinal malignant tumors.  Carcinoid tumor size when first diagnosed is very important since the likelihood of having the tumor already spread is in direct proportion to its size.  If the carcinoid is greater than 2 cm in diameter (almost 1 inch) chances of spread increase to greater than 50% then those carcinoids discovered when smaller.  Initially carcinoid tumors grow into the wall of the intestine from the lining where the carcinoid began but if allowed to grow untreated a carcinoid may go through the wall and then extend into nearby lymph nodes, lymph channels, and blood vessels and can later spread to more distant locations such as the liver, lungs, bone, skin, brain and even the heart.

Approximately 20% of the small intestine carcinoid tumors will spread to distant locations (metastases) and roughly 1/3 of carcinoids that have spread will develop symptoms of what is now known as Carcinoid Syndrome.  The majority of carcinoid syndrome patients (66%) have the carcinoid originate from the gastrointestinal tract. Carcinoid tumors of clinical importance occur in various locations listed below from site of most frequent occurrence to least frequent:

• >30% Small Intestine
• >25% appendix
• >10% rectum
• 10% bronchial system of the lungs
• <10% colon, stomach, pancreas, liver

While rare, carcinoid tumors may also arise in locations such as gallbladder, bile ducts, ovaries, testicles, urinary bladder, prostate gland, breast, kidneys and the thymus gland; extremely rare cases have arisen from both the eye and the ear.
Up to 25% of all GI tract carcinoid tumors are associated at some time with another tumor of non-carcinoid type, such as the colon cancer, lung cancer, breast cancer or prostate cancer.  Of all carcinoids, those arising in the appendix are the most benign, rarely spreading and >80% of people with carcinoid of the appendix diagnosed and removed by surgery remaining alive for 5 years post-surgery. A carcinoid is found usually by accident in 1 of every 200-300 appendices removed at surgery.
The second most benign carcinoid tumor are rectal carcinoids with a >70% 5 year survival post-surgery.  However, if metastases are present when a carcinoid from any site of origin is found, the 5 year survival rate drops to <30% if not treated.

Carcinoid tumors originating in the stomach (gastric carcinoids) occur as one of three types:

1. Carcinoids associated with pernicious anemia or other conditions causing degeneration of the stomach lining with a loss of normal gastric acid production.   These are usually multiple, small and even microscopic carcinoids which infrequently spread and are rarely fatal.  These carcinoids may sometimes be made to shrink and even disappear by surgical removal of the gastrin hormone producing end portion of the stomach.  In some cases medical treatments can control and reverse carcinoid growth.

2. A very few gastric carcinoids can occur as part of Multiple Endocrine Neoplasia (MEN) syndrome. These carcinoids are usually very slow growing and have low grade malignant potential.  They are associated with other endocrine gland tumors in other organs.

3. Sporadic carcinoids, i.e. carcinoids that occur in the stomach as single or occasionally several tumors without a special predisposition, just like carcinoids elsewhere in the intestine. These carcinoids can slowly grow large and occasionally cause discomfort or bleeding or, in about ½ the cases, spread in a malignant fashion.

Carcinoids of the lung (bronchial carcinoid) are often associated with their own special peculiarities, diagnostic modalities and forms of treatment. An excellent overview of carcinoid tumors can be found on the American Cancer Society's website:  Lung Carcinoid Tumor Information.
 
Carcinoid Syndrome
Carcinoid cells can produce hormones.  Those carcinoid tumors which produce large amounts of hormones and other potent chemical substances, and which are usually found to have spread to the liver, may cause a hot red flushing of the face, diarrhea, and asthma like attacks.  These episodes, referred to as carcinoid crisis, may be infrequent at first but increasingly will occur more often and are usually associated with abrupt low blood pressure and even fainting.  Alcohol or stress (physical or emotional) sometimes provokes attacks of carcinoid crisis and they may also occur spontaneously.  After a time, the flush may become persistent in some individuals with carcinoids and may not be felt or noticed by them.  The diarrhea may become chronic with resulting weight loss.  Heart valve damage and other cardiac changes can occur in some carcinoid cases.  All of the above features make up parts of the Carcinoid Syndrome.
 
The potent chemicals and hormones made by the functioning carcinoid tumors (as opposed to the more frequent non-functioning carcinoid tumors; i.e., carcinoids that do NOT produce hormones), through their effects on the cardiovascular, gastrointestinal, pulmonary and other systems of the body, cause the Carcinoid Syndrome.  In many cases the symptoms of the Carcinoid Syndrome resulting from the hormones and chemicals produced are worse than the symptoms from the growth of the tumor itself.
Not all functioning carcinoid tumors produce the same large variety of chemicals and hormones and it is not yet entirely clear as to which of the substances are responsible for each of the symptoms of the Carcinoid Syndrome.  However, almost all of these tumors make one or more of serotonin, bradykinin, and chromogranin-A.