January 2009
This document was prepared in order to further the Carcinoid Cancer Foundation's
educational goals and inform you about the existence and characteristics
of carcinoid cancer. While the information contained herein represents
up to the minute information about carcinoid cancer, it is not to be used
as a substitute for a visit with your doctor if there is any question about
your condition.
NOTE:
After reading this basic essay about carcinoid cancer, you may have many unanswered questions. We suggest you then proceed to the page: Frequently
Asked Questions . or call the CCF staff Tuesday - Thursday 10am -4pm 888-722-3132 or email us at carcinoid@optonline.net
If you find many new medical terms that are unfamiliar to you, visit the medical glossary page for an explanation.
In order for an answer to these questions to be meaningful to you, you
must first understand some basic concepts about the body and how tumors
develop and grow. Every part of the body from the skin to your heart, muscles,
glands and all other organs, is composed of microscopic cells just like
the bricks that make up the structure of a building, but unlike building
bricks the body's cells are formed in classes specialized in appearance,
structure and function for the purposes of the organ or the part they form.
Furthermore, unlike the bricks of a building, which once formed and set
in place are unchanging for the life of the building, the living cells
of the body are constantly degenerating, wearing out, and being regenerated/replaced
by identical cells. This replication process is going on continuously and
is regulated by complex genetic and hormonal controls from both within
the individual cells and also by influences from other parts of the body.
When something goes wrong with this delicate, complex regulatory system,
cell replication sometimes proceeds unrestrained and then a tumorous growth
(neoplasm) is formed by that one type of cell overgrowing. If this overgrowth
is somewhat limited and does not spread to other areas or threaten to squeeze
out or replace adjacent structures, it is considered to be a benign tumor,
that is, not life threatening. However, if the growth is more aggressive
and threatens surrounding tissues or sends "seedlings" (metastases) to
grow in distant areas then it has potential to be fatal and is considered
malignant; that means it is a cancer
There are a few types of growths that are sort of mid-way between these
two classifications of benign and malignant. Carcinoid tumors are the most
often occurring of these rare types of "midway" growths. They have been
called "cancers in slow motion" because even though they usually have the
potential for ultimately being fatal, they mostly tend to grow so slowly
that people afflicted with these tumors usually live for many years, indeed
sometimes for a normal life time. The wide variety of treatment now available
makes the outlook for most victims of the more aggressive carcinoids more
hopeful than it used to be - but more on this later.
Relative newcomers to medical recognition, carcinoid tumors were first
identified as a specific, distinct type of growth in the mid 1800's, and
the name "carcinoid" was first applied in 1907 by Oberndorfer in Europe
in attempt to designate these tumors as midway between carcinomas (cancers)
and adenomas (benign tumors).
They were found to arise from enterochromaffin cells (glandular endocrine-hormone
producing cells) widely distributed in the body but found in greatest amounts
in the small intestine and then in decreasing frequency in the appendix, rectum,
lung, pancreas and very rarely in the ovaries, testes, liver, bile ducts and
other locations. These cells have special peculiar features that make them identifiable
under the microscope. They stain in a special way when put in contact with silver
containing chemicals. Special stains for the particular hormones that enterochromaffin
cells can make will identify the hormone substances in carcinoid tumor cells
and thereby confirm the diagnosis of the microscopic exam on biopsied carcinoid
tumors.
Only as recently as 1954 was the Carcinoid Syndrome first described
and accepted as a specific disease entity. Thorsen, Biorck, Björkman
and Waldenstrom, a group of doctors in the United States and Scandinavia,
first recognized the nature of the various symptoms associated with some
carcinoid tumors that have become known as Carcinoid Syndrome and they
described it in a medical journal. This syndrome, which I will discuss
in more detail later, consists of a group of symptoms and findings on physical
and laboratory examination that are sometimes caused by the potent hormones
produced by carcinoid tumors.
In the early 1990's the development and availability of octreotide (Sandostatin)
by the Sandoz Pharmaceutical Company ( now Novartis) provided a most important
drug for the treatment of the Carcinoid Syndrome and for carcinoid tumor disease
in general. This drug is derived from the naturally occurring hormone somatostatin.
Along with this, Novartis aggressively educated doctors about the rare carcinoid
tumor and syndrome and this has done much to increase awareness of the condition
and to enhance its diagnosis and treatment. In Europe and some countries in
other parts of the world one of two other somatostatin derivatives, lanreotide(Somatuline)(Ipsen) and vapreotide (Sanvar® IR , are also used.
Large studies of many individuals indicate that the occurrence of insignificant
small carcinoids that seem to last a lifetime and cause no problems and
do not spread is fairly common, occurring in approximately 1 out of every
100 individuals. The most common location in which carcinoids form is
in the small intestine. Tumors of any kind in the small intestine are rare
and comprise only 1% of all the cancers of the gastrointestinal tract.
However, carcinoids of clinical importance (not the tiny coincidental tumors
mentioned above) comprise about 50% of all small intestinal malignancies.
Their size when first diagnosed is very important since the likelihood
of having already spread is in direct proportion to their size. If the
tumor is greater than 2 cm in diameter (almost 1 inch) chances of spread
are greater than 50%. Initially the carcinoid tumor just grows into the
wall of the intestine from the lining where it starts. However, eventually
it 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% (1/5) of the small intestine carcinoids will develop distant
spread (metastases) and roughly 1/3 of those that have spread will develop symptoms
of the Carcinoid Syndrome. From these numbers it is apparent that the Carcinoid
Syndrome is very rare. Currently in the United States approximately 5 new
clinically significant carcinoid cases are diagnosed each year per 100.00
individuals in the general population. In about 2/3 of these cases the carcinoid
arises from the gastrointestinal tract. The occurrence of carcinoid tumors of
clinical importance according to the location of origin breaks down as follows:
39% small intestine
26% appendix
15% rectum
10% bronchial system of the lungs
5-7% colon
2-4% stomach
2-3% pancreas
>1% liver
There are also some very unusual and extremely rare locations from which carcinoids
may arise or to which they have spreadand they are: the gallbladder and bile ducts, the ovaries, the testicles,
the urinary bladder, the prostate gland, the breast, the kidneys and the thymus
gland and in some very rare cases of the eye and the ear.
Up to 25% of all GI tract carcinoids are associated at some time with another
tumor of non-carcinoid type, such as the typical colon cancer, cancer of the
lung, breast cancer and prostate cancer. Of all carcinoids, those arising in
the appendix are the most benign, having only very rare distant spread and 87%
of people with carcinoid of the appendix diagnosed and removed by surgery remaining
alive after 5 years. A carcinoid is found usually by accident in 1 of every
200-300 appendices removed at surgery.
The second most benign of these tumors are the rectal carcinoids with a 72%
5 year survival. If distant metastases are present when a carcinoid from any
site of origin is found, the 5 year survival rate drops to 27% if
not treated.
Gastric carcinoids; Carcinoid tumors originating in the stomach are sometimes
very special. These gastric carcinoids occur as one of three types:
1. Those associated with pernicious anemia or other conditions
causing degeneration of the stomach lining with
loss of normal gastric acid production. These are usually multiple, small
and even microscopic carcinoids which infrequently spread and rarely are fatal
and sometimes can be made to shrink and even disappear by surgical removal of
the gastrin hormone producing end portion of the stomach. In some cases sandostatin
and other medical treatments can control and reverse these growths.
2. A very few gastric carcinoids can occur as part of the
MEN syndrome. These 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. Those can slowly grow large
and occasionally cause discomfort or bleeding or, in 50% of 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 summary of this subject can be found on the American Cancer Society's
website: Lung
Carcinoid Tumor Information.
Carcinoid cells can make 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, can cause hot red flushing of the face, diarrhea,
and asthma like wheezing attacks. These episodes of "carcinoid crisis" may be
very infrequent at first but gradually occur more often and are usually associated
with abrupt low blood pressure and even fainting. However, in a few cases the
attacks are accompanied by high blood pressure. Alcohol or stress (physical or
emotional) sometimes provoke attacks but they often occur spontaneously. After
a while the flush may become persistent in some individuals and may not be felt
or noticed by them. The diarrhea may also be chronic and weight loss can occur.
A specific type of heart valve damage can occur in some cases as well as other
cardiac disturbances. All of these features constitute the Carcinoid Syndrome.
The potent chemicals and hormones made by the "functioning" carcinoid
tumors (as versus the more frequent "non-functioning" carcinoid tumors),
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 Serotonin, bradykinin,
and chromogranin-A. Other substances whose names you may sometimes come
across in connection with these tumors and which are often made in association with carcinoids
are: substance-P, neurotensin, pancreatic polypeptide, neurokinin-A, motilin and atrial natriuretic hormone (ANH), as well as other peptide hormones.
Carcinoids belong to a group of growths called neuroendocrine tumors.
Each type of neuroendocrine tumor produces a different main hormone and
hence a different syndrome - that is, it causes different symptoms. Why
is this important for us to include in a discussion of carcinoid? First,
and most important, each of these syndromes, though having different features,
can prominently include flushing and/or diarrhea and be confused with Carcinoid
Syndrome. Secondly, a carcinoid can occasionally have "mixed" function
causing one of these other syndromes along with Carcinoid Syndrome. This
is the result of the carcinoid producing one or more of these other hormones
along with production of its own specific hormones. Thirdly, an inherited
familial (genetic) condition 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 neuroendocrine
tumors. This is called MEN ( multiple endocrine neoplasm )syndrome.
Non-functioning carcinoid tumors are so slow growing that many years may
pass between the onset of any symptoms and the diagnosis. They can cause
intermittent abdominal pain and then a change in bowel habits that may
lead to intestinal obstruction. In some cases they cause obscure intestinal
bleeding or sometimes don't declare themselves until they cause painful
enlargement of the liver due to large deposits of carcinoid metastases
that have spread to that organ. The diagnosis is not usually suspected
prior to surgery but is then established by biopsy.
The Carcinoid Syndrome, due to the presence of a functioning carcinoid tumor,
is easily diagnosed when all the features of the syndrome are present or even
when 1 or 2 of the main symptoms are present and the Carcinoid Syndrome is thought
of. The biggest impediment to making the diagnosis is not thinking of the Carcinoid
Syndrome, or even considering it because of its rarity. Once considered, the
diagnosis usually can be confirmed quickly and painlessly by doing a urine 5-HIAA
test. This stands for 5-hydroxy indole acetic acid which is the main breakdown
(waste) product of Serotonin. Its quantitative measurement in the urine which
an individual excretes in a 24 hour period tells how much Serotonin is being
made in the body during that time. In the presence of Carcinoid Syndrome the
amount of 5-HIAA is almost always distinctly increased above normal. Certain
foods and medicines must be avoided for a day or two before, and on the day
of the urine collection, since they can cause false test results. These are:
bananas, pineapple and its juice, red plums, avocado, walnuts and other nuts, kiwi fruit, tomatoes,
various cough medicines muscle relaxing medicines, acetaminophen (Tylenol),
caffeine, fluorouracil, iodine solutions (Lugol's solution), phenacetin, MOA
inhibitors (certain antidepressant drugs), isoniazid, and phenothiazine drugs
(Compazine, Thorazine). For more information how to prepare for a 24 hour urine test click here. Sometimes urine 5-HIAA is not increased but other carcinoid
"markers" in the blood can be measured and will be increased. These are chromogranin
A (CgA) and serotonin. Blood tryptophan will be decreased below normal values.
The measurement of CgA is considered "the gold standard" of chemical
tests for confirming the diagnosis of carcinoid and neuroendocrine tumors and
following their course.
Standard X-ray and imaging techniques can be helpful in finding a carcinoid
tumor and identifying its spread. This could include routine chest X-ray,
CT scans, MRI, barium enema and upper GI and small bowel X-ray studies.
Sometimes upper and lower GI tract endoscopy (looking inside the body with
a flexible fiber optic tube through which biopsies can be taken) is also
helpful.A now universally approved (though costly) way of finding carcinoid tumors,
as well as other neuroendocrine tumors, is the OctreoScan
It is successful in 85% of carcinoids and consists of a harmless injection of
a minute dose of a short duration radioactive isotope which is specifically
attracted to, and concentrated in, carcinoid tumor tissue (and any other neuroendocrine
tumor) where it lights up when a radiation scan is taken over the entire body.
It is dissipated in a few days, and again I emphasize it is harmless. OctreoScan
should be done in almost all cases even when the diagnosis is known. This is especially
important in those cases where standard imaging (i.e. CT-scans, MRI) and chemical
markers have failed to reveal the diagnosis and location of tumors. There are
occasional cases in which all the symptoms and chemical findings of Carcinoid
Syndrome are present but standard tests fail to reveal a tumor. In these cases
octreoscan can be a great help in confirming the diagnosis and locating the
tumor(s). A positive octreoscan usually predicts a good response to treatment
with octreotide.(Sandostatin)
Typical carcinoids are slow growers. Data on survival of patients with
small tumors not causing Carcinoid Syndrome and without spread, treated
by surgical removal alone, indicates that a complete cure is usually possible
in these cases.
In those tumors that are somewhat larger and have spread to local tissues
and local lymph nodes but which, along with these locally invaded tissues,
are still totally removable surgically, the average survival has been 8
years with a range up to 23 years.
Even when the tumor from the small intestine has spread in a manner that has
made complete surgical removal impossible, the older statistics show that approximately
one half of the patients survive an average of 5 years. Since various types
of treatment have been introduced in the past decade patients appear to have an
even longer survival and improved quality of life.
Atypical carcinoids, which is a group whose microscopic appearance looks
different and more aggressively malignant than the typical carcinoid, follow
a much more rapid course with a more uncertain outlook. An even worse forecast
can be made for the very more malignant rare group called "neuroendocrine carcinoma". Atypical carcinoids can cause the
Carcinoid Syndrome, but neuroendocrine carcinoma rarely do.
The tempo of the course of the illness in patients with Carcinoid Syndrome
is different than that of carcinoid victims without the functioning syndrome.
However, this has been remarkably improved and the outlook is much more
hopeful with the advent of octreotide and similar somatostatin analogues and other new modes
of treatment. In the early decades before effective treatment was available
the average survival from the onset of flushing for a Carcinoid Syndrome
patient was 3 years, and from the time of diagnosis was 2 years, though
the range extended to over 10 years. Seventy five percent of the patients
would die as a consequence of the harmful effects on the body from the
excessive amounts of potent hormones released into their circulation by
the tumors. Tumor growth and spread itself was fatal in only 25% of cases.
In the last 10 years, since we have used effective combinations of treatment
with octreotide(and similar somatostain analogues), various types of surgery, chemotherapy, hepatic artery
injections and biological response mediators, the average survival time
from the start of treatment (which unfortunately is often quite delayed
after the diagnosis is made) has increased to almost 12 years - with
a wide range often being observed.
Carcinoid tumors vary greatly in their size, location, symptoms and growth.
Therefore the treatment in each case should be individualized to what is
best for each particular patient.
Surgery, with complete removal of all of the tumor tissue, is the first and best treatment
when it is possible, and if detectedearly can result in a complete and permanent cure. However,
even when all tumor tissue cannot be removed, surgery may be necessary for various
purposes such as relief of intestinal obstruction or control of intestinal bleeding.
When the Carcinoid Syndrome is present, removing or destroying large portions
of the tumor (debulking) can effectively diminish the amount of harmful hormones
being produced and flooding the circulation. Because of the slow growth of most
carcinoids, this can relieve symptoms for a long time. Technique of using a freezing
probe (cryoablation) or Radiofrequency ablation (RFA) are now used at
major medical centers to destroy carcinoid tumor metastases in the liver when
it has not been possible to excise them surgically. Another way to debulk unresectable
carcinoid tumors that have spread to the liver is to inject the liver artery
supplying blood to the metastases with a combination of embolic material and
chemotherapy drugs. This shuts off the blood flow with its oxygen supply to
the tumors and also loads them with tumor destroying and growth inhibiting chemotherapy.
Thus this chemotherapy is concentrated in the tumors where it can have a much
greater effect than in the rest of the body. However, opinion is divided regarding
whether chemotherapy injection with embolus is of greater benefit than embolus(bland embolization)
alone.
Chemotherapy for carcinoid given by intravenous injection or by mouth has been
in use for over 20 years. There are many drugs available. Individual drugs used
alone have been disappointing but a number of combinations of these drugs have
been beneficial. Some of these combinations are: leucovorin-fluorouracil and
streptozotocin, cytoxan- Doxorubicin and cisplatin, dacarbazine-fluorouracil,
etoposide-cisplatin. One or another of these combination has produced good response in only 20-30%
of the cases. Fortunately however, those patients in whom one chemotherapy routine
is ineffectual may respond well to one of the other drug combinations. In other
words, failure to respond to one combination does not necessarily mean another
combination of chemotherapy will also be ineffectual. The site of the origin
has considerable influence on likelihood of the tumor(s) responding to chemotherapy.
For instance pancreatic and lung carcinoids respond to some forms of chemotherapy
better than intestinal carcinoid.
A number of newer drug combinations are currently
being investigated.(RAD001), Sorafenib (Nexavar).Sunitinib (Sutent), Atiprimod, SOM 230, Avastin (Bevacizumab),Temozolomide (Temodar), Capecitabine (Xeloda®), and others.
Somatostatin analogue (octreotide/lanreotide and vapreotide) injections not only usually squelch the symptoms of
Carcinoid Syndrome but are now believed to sometimes inhibit or even reverse
growth of the tumors. This has become the mainstay of treatment for most
carcinoid tumors, with or without the Carcinoid Syndrome. Somatostatin analogues (octreotide/lanreotide/vapreotide) are now available in the US and other countries in three forms; octreotide- trade name - Sandostatin s.c.®, and Sandostatin LAR®(given every 3 -4 weeks) manufactured by Novartis, lanreotide - trade name - Somatuline®, manufactured by Ipsen/(In the US contact Tercica). In a few patients
needing large amounts of octreotide continuous injection of Sandostatin s.c. is given by a special tiny injection pump
as is used for insulin in some diabetics. (see paper by Dr. Eugene Woltering ..Click Here)
Patient Assistant Program (PAP) by Novartis Pharmaceuticals Novartis Pharmaceuticals Corporation's Patient Assistance Program (PAP) provides assistance to patients experiencing financial hardship who have no third party insurance coverage for their medicines. For more information, about this program and insurance
reimbursement issues, call their Hotline 1-800-282-7630. For information about Sandostatin LAR® Depot reimbursement, visit
their website.
Throughout the world, approximately 8-12 dozen patients with carcinoid metastases
to the liver and no discernible tumors outside the liver have undergone liver
transplant. Their survival has been about equal to those patients with equivalent
disease treated by the more conventional means outlined above. At this time
I do not see a role for this extremely expensive and debilitating treatment
in any but the most extraordinary carcinoid case.Interferon is a natural substance originally derived from white blood cells
that inhibits growth of carcinoid and certain other tumors as well as certain
viruses. There are several varieties of interferon (Intron A and Roferon A) of which the alpha form has
seen the most use for treating carcinoid and is commercially available. Drugs of this class are considered "biologic response mediators" or "immunomodulators"
rather than tumor cell poisons (cytotoxins) such as chemotherapy drugs. Though
beneficial in suppressing tumor growth in at least half the carcinoid patients
treated, interferon often causes unpleasant side effects of extreme fatigue
and flu like symptoms. Side effects are often avoided or reduced by using low
doses of this medicine which even then can often be effective.
Radiotherapy in carcinoid is useful only in pain relief and regressing tumors
when they have spread to the skeletal system and when causing severe pain. Radiation
treatment to the specific painful spot will usually provide relief. It has not
been useful in treating metastases in the liver or in other non skeletal tissues.
Experimental studies are underway, using internally injected radioactive isotopes
in selected carcinoid patients, in a number of research centers abroad.
The current favored isotopes are Yttrium 90 (Y90), Lutetium 177 and Gallium 68. Increasing evidence of the effectiveness of these very expensive treatments is emerging and efforts to start their use in the US are under way. An additional new treatment for liver metastases emerged during the past 5-6 years and consists of injecting the hepatic artery with radioactive isotope Yttrium 90 impregnated microsphere emboli.(Therasphere, SirSpheres) Initial results are very promising. This is meeting with considerable success when the sole or dominant site of metastases is located in the liver.
Narrow beam radiotherapy such as CyberKnife, is being tried in a few places but has not yet been clearly shown to be of value.
Besides the various anti-tumor treatments reviewed above, there are many
benefits resulting from a nutritious high protein diet, vitamin supplements
- particularly niacin, mineral supplements (such as potassium, magnesium,
calcium, iron and even salt) when these are deficient due to diarrhea.
In addition to the use of Octreotide or Lanreotide to control diarrhea, conventional
anti-diarrheal medications such as Lomotil and Imodium may be helpful.
Cyproheptadine (Periactin) may also help the diarrhea as well as flushing.
Large portions of freshly grated nutmeg (1 teaspoon eaten 3 times a day)
will sometimes control the diarrhea remarkably well. Antihistamines and
alpha adrenergic blocking drugs such as Dibenzyline are sometimes used
to prevent Carcinoid Syndrome attacks. All carcinoid patients should avoid
alcoholic beverages and physical and emotional stress since these can precipitate
carcinoid crisis attacks. Similarly, adrenaline like drugs should be avoided.
These include various asthma inhalers, nasal decongestants and adrenaline
itself. Certain very severe and prolonged carcinoid crises associated with
bronchial (lung) carcinoids or some carcinoids of the stomach are responsive
to treatment with corticosteroids (prednisone, Decadron) and Thorazine
or Compazine.
As you can see there is good reason to be hopeful. There are abundant treatments
for carcinoid tumors and syndrome though choice of treatment and their applications
can be quite complex. Even though this is a rare disease there are experts available
who are interested and willing to help and a great deal of research is in progress
which promises additional effective therapy in the foreseeable future. See list of experts and other physicians diagnosing and treating carcinoid patients.
Richard
R.P. Warner, M.D.
Medical Director of the Carcinoid Cancer Foundation TM
Professor of Medicine
Mount Sinai School of Medicine, New York City
CV
The Carcinoid Cancer Foundation, Inc.
333 Mamaroneck Avenue # 492
White Plains, NY 10605
Tel: (888)722-3132 or (914)683-1001
Fax: (914)683-1083
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