Gastrointestinal Stromal Tumor (GIST)

What is it?

GISTs are sarcomas of the digestive tract. They can appear on any point alongside it, from the esophagus to the anus. Digested matter always goes through from the mouth to the anus, and never in the opposite direction, because the digestive tract concentrically contracts ceaselessly all across its longitude, in a way that the closest parts to the mouth contract first and the farthest later. The resulting effect is the same that we would get hugging firmly a toothpaste tube between our index and our thumb forming a ring, and sliding them alongside the tube towards its opening end. This successive waves of contraction and relaxation that propel the intestinal content one way only, are known as peristaltic waves and happen automatically all the time.

For the intestine to work that way it requires the existence of its own nerve system so it can coordinate the contractions, making sure they do not happen disorderly, but in the right time and with the right intensity, velocity and direction. This nerve system, proper of the digestive tract only, is formed by a particular type of cells that connect to each other making a net that surrounds the tube from top to end. Such nerve cells were identified during the last century by the Spanish histologist Santiago Ramón Y Cajal and that is why they are known today as the Cajal Interstitial Cells. Nowadays we suppose that those cells can become cancerous and that when they do, the type of cancer they originate is, precisely, GIST.

For many years we have mistaken GIST with intestinal leiomyosarcoma, a cancer created by the malignant transformation, not of the nerve cells in the intestine, but of the muscular ones. Both types of cells are so similar that both cancers are almost undistinguishable even for the most thorough microscope examination. However, the difference is crucial, as GIST is very sensitive to Imatinib treatment, while leiomyosarcoma is completely resistant to its effects. We oncologists had not been able to differentiate both types of cancer until we properly understood how GIST appears.

How it appears?

A cell with this kind of mutation on its c-KIT could be compared to a car with a fully pressed stuck accelerator and broken brakes running towards a cliff called cancer.

The GIST’s molecular key is called KIT. This molecule traverses the cell membrane, with one of its ends outside and the other one located on the inside. The external part acts as an antenna; in the presence of certain stimuli, it sends a signal to the opposite end of the KIT, the one inside the cell, which activates it. The KIT’s activation produces a series of chemical reactions inside the cell that modify it radically in two different ways. In the first place, it starts multiplying itself at a very high-speed; one cell turns into two, two into four, four into eight and so on. Secondly, these multiplying cells are immortal; their life is not limited by a finite number of cycles.

These two characteristics, exponential proliferation and unlimited life, are essential in the initial phases of any cancer. Having the KIT activated is dangerous, it is similar to a car with a fully pressed accelerator. Some tissues might require the KIT function but they usually keep the molecule in a secure disconnected situation. Our cells keep the KIT in line in two ways. Firstly, the stimuli that activate the KIT are very brief so it instantly feels the absence of the stimuli (the feet leave the gas pedal), reestablishing the usual disconnection. Secondly, there are other molecules inside every cell with KIT in charge of looking after and disconnecting it if it is activated for too long (which is the equivalent to pressing the brake). The exact functions of KIT in the human organism are not still completely known but, we do know that it appears in some cells, such as the skin, bone marrow and the digestive tube’s interstitial cells.

KIT is a protein, and just like every other protein among the hundreds that make our body work every day, it is codified by a gene, a DNA fragment containing the exact recipe with which the cell synthesizes the protein. C-Kit is the gene that codifies the synthesis of the KIT protein (consider that genes and proteins often have the same or a similar name; however, the gene is written in lower case while the protein is written in capital letters). In 1990, it was proved that some mutations in the c-Kit generated defective KIT proteins. These mutants stayed active all the time, even in the absence of any stimuli. And what is even worse, they are immune to the control mechanisms to disconnect the KIT healthily. A cell with this kind of mutation on its c-KIT is similar to a car running with a fully pressed stuck accelerator and broken brakes towards a cliff called cancer.

Everything said before refers to the GIST appearance mechanism but does not clarify its causes. In order to elucidate it, we would need to find out what causes the c-Kit gene mutation in the first place. It might be the toxins contained in the food, a virus infection, just a random mistake in the regular copying process of genes, or all of them together. Naturally, lacking any clue about the causes, there is no chance of preventing it.

INTRO:

To sum up, in a certain moment of a person’s life there is something wrong in one of the interstitial cells of Cajal that regulate intestinal movement; the c-Kit suffers a mutation and the cell starts producing the wrong molecules of the KIT protein, which remains active all the time, so the cell multiplies unstoppably and indefinitely failing in disconnecting KIT. It rushes into a malignant transformation and a GIST appears somewhere in the digestive tube. Sometime after that, the individual starts feeling the first symptoms. 

How does it manifest?

The more we study the GIST, the more often it seems to appear. Currently, it is calculated that around 600-800 new cases appear in Spain every year. It is an incidence far from other tumors in the digestive tube but similar to other diseases that are not considered rare at all, such as chronic leukemia. As well, we should take into account the number of previously diagnosed cases as leiomyosarcoma that with today’s technology turned out to be GIST. Something is happening. It was thought that among the intestinal sarcomas, leiomyosarcoma were the most frequent, while GIST was hard to find. However, more and more centers are recovering old files with leiomyosarcoma biopsies that under the new criteria turn out to be GIST.

Turning the tables, the real leiomyosarcoma turns out to be getting more and more uncommon, while the GIST becomes the most frequent variety of abdominal sarcoma. The practical result is that every former patient undergone through any kind of abdominal sarcoma years ago and currently suffering a relapse, it is mandatory to perform the right tests to ensure it was not a GIST from the beginning. If the old biopsy wasn’t locatable, the implications are so large that it would be completely justified to do a new biopsy of the relapse.

The onset of GIST is usually over 50 years old, appearing in the same proportion of men and of women. The most frequent place where it may appear is the stomach, followed by the small intestine. Just a 20% appears somewhere else: in the esophagus, colon, or rectum. Exceptionally, it might also appear inside the abdominal cavity, separated from the intestine. Unfortunately, the GISTs’ soft consistency does not usually impede the intestinal transit or other organs functioning; which means that symptoms won’t appear while the tumor is in a locatable, operable and curable stage.

In many cases, the disease does not become apparent until an advanced stage in which the cancer has already spread through the abdominal cavity or reached places like the liver as a metastasis. If it is not the case, it is not possible to make a diagnosis until the tumor has grown so much that it produces discomfort in the casing. The most frequent symptom is the abdominal pain, which starts as a mild discomfort and worsens as months, or even years, pass by. If the tumor forms an ulcer inside the bowel, blood can appear in the stool or vomits or, most likely, cause anemia due to the prolonged loss of small quantities of blood mixed in the deposition. In some cases, the symptoms may depend on the location of the metastasis inside the abdomen. Some of them are diagnosed when the tumor breaks, bleeding inside the abdominal cavity (usually after a traumatism). 

How can you make a diagnosis?

It is nearly impossible to suspect the existence of a GIST due to its peculiarity and bland symptoms. Anyway, in order to dismiss any chance of having a tumor inside the abdomen, the doctor will order a scan, an ultrasound or an endoscopy. If there is such a tumor and it looks removable, the doctor will perform a surgical intervention. On the contrary, if it is not possible to operate on the tumor because of its size or the existence of metastasis, a biopsy will be prescribed. Either way, a sample of the tumor will go under the pathologist’s microscope. In case it was a sarcoma, the pathologist would carry out a special staining that will reveal whether it is a GIST.

This type of staining is called immunohistochemistry which is based on the relationship between the GISTs (unlike other similar tumors) with KIT. The sample contacts the antibodies designed to react and attach to the KIT protein on the cell’ surface. The binding of the antibody and KIT produces a noticeable color change under the microscope. In this case, the pathologist will identify the tumor as ‘KIT-positive’, finishing the GIST diagnosis. A 5% of the cases turn out to be ‘KIT-negative’ i.e. there is no staining in the immunohistochemistry. In these cases, the biopsy can be sent to some of the few centers in Spain studying the existence of mutations in the two genes involved in originating the disease. One of them, as we have said before, is the c-Kit, while the other is called PDGFRA.

As with any other cancer, once the doctor has received the diagnosis, he will complete it with x-rays, ultrasounds and scans of different organs to determine the range of the disease and plan a treatment. 

How is it treated?

The classic and only treatment to successfully cure a GIST is surgery. However, as we have seen before, there are many cases no longer operable when diagnosed. Furthermore, a significant percentage of the patients undergone through a GIST surgery relapses over time. Most of these relapses happen within the first two years after the intervention, even though some relapses were documented up to 20 years after the it.

The chance of a relapse depends on the size of the tumor and the number of mitoses (the quantity of dividing cells observed under the microscope). The GISTs under two or three centimeters and little or no metastasis relapse so rarely that they are almost considered benign. Instead, tumors over 10 centimeters or with numerous mitosis end up causing metastasis in most cases. The GISTs located in the stomach have less chances of a relapse than tumors somewhere else. Currently, many research resources are being dedicated to the individual study of each genetic mutation to find out if they can help distinguish which are the ones doomed to relapse and which ones are truly cured.

The tricky issue is whether consuming imatinib after removing a GIST with a high-risk of a relapse might partially counteract that danger. The results obtained through the research conducted over this issue have been strong enough to get the acceptance of the European and American health authorities for this new use of the drug. In other words, nowadays imatinib is no longer used just for the disease’s treatment but, for increasing the expectations of the people already operated in a high risk of relapse. These poor prognosis factors are usually big sized tumors and an abundance of mitosis.

However, the results obtained from the clinical trials have proven that the treatment can actually delay the relapse, although its ability to prevent them remains uncertain. A patient’s lifetime might be exactly the same if the relapse was delayed by administrating the drug after the surgical intervention as if the treatment did not start until the relapse. There are other questions regarding the treatment’s optimum duration, choosing the ideal cases or the chance of developing stronger relapses after the imatinib treatment. Fortunately, there are ongoing clinical trials that will resolve these issues in the years to come.

Meanwhile, whether a GIST operated on a patient should or not consume imatinib for at least one year is a decision that must be agreed by both the doctor and the patient after conducting a deep research and considering each person’s risk of relapsing.

The danger of a GIST relapse increases if it breaks inside the abdominal cavity during its removal. That is why the laparoscopic surgery (using tubes introduced int the abdomen, which will be closed during the intervention) must be prescribed very carefully and by experimented surgeons. Furthermore, if the surgeon considers that the risk of breaking the GIST during the removal is too high, the patient can start an imatinib treatment, leaving the operation for some months later when the tumor becomes smaller and the removal, safer.

The GIST common representation is such a developed tumor inside the abdomen that it becomes impossible to remove either because of its size or the existence of a metastasis in other organs. Until 2001 there was no effective treatment. Nowadays, all patients are treated with imatinib. 

What can you get from imatinib treatment?

Imatinib is the ideal treatment for disseminated GISTs with metastasis inside the abdominal cavity or in organs such as the liver. The treatment cannot eradicate the tumors completely, so it is not an alternative to surgery for the patients able to deal with it. However, the treatment is a choice for those who, despite being operable, surgery is contraindicated by their health or age.

Imatinib appears in the form of hard orange capsule of 100 or 400 mg each, called Glivec® (Novartis). The dose is 400 mg per day, either in one daily dose or two 200 mg doses. Some special cases require an initial daily dose of 800 mg. The tablets must be swallowed with the meals and a big glass of water since they might irritate the gastric mucosa. It is important to tell the doctor about any other medication being consumed because some drugs reduce its absorption, while others increase it. The oral administration should not lead to misunderstandings about imatinib; it is a complicated drug for a complicated disease. No intern, general practitioner or surgeon must use it. Any GIST patient treated with must be under an oncologist’s continuous direct control.

Every inoperable or metastatic GIST patient must receive an imatinib treatment, regardless of how advanced the range of the disease is or how impaired the patient is. Its adverse effects are infinitely minor than the chemotherapy’s and the first improvements might appear during the first week of treatment. No GIST patient is too old or too critical not to be worthy of the imatinib treatment. In a 40 or 50% of the cases treated with Gliver®, the disease stops growing and starts reducing its size. In another 25-30% of the cases, the tumor stops growing and stabilizes. The patient’s life prognosis whose tumors are reduced and those that just stop growing are almost the same. Just those in which the GIST grows in spite of receiving the treatment have negative expectations.

The decrease of their size is usually slow but constant. In many cases, the tumor and the metastasis’ volume continue to decrease gradually even months after starting the treatment. The duration of the answer is much longer than the cancers treated with chemotherapy. More than half of the patients that started imatinib more than 5 years ago haven’t worsened. Regarding the treatment’s duration, we know that if it is interrupted, the GIST starts growing again one or two months later. Thus, the treatment’s duration must be indefinite.

In some cases, a GIST inoperable patient might experience such a decrease in the tumor’ size that the imatinib treatment would lead to an accessible complete removal. Actually, we don’t know if the surgery offers any advantages over just continuing the treatment. Some studies are being performed to solve this question. In the meantime, both options are correct. It is essential to perform an exhaustive study to dismiss the existence of any hidden metastasis if you chose to have a surgery. 

What are the adverse effects of imatinib treatment?

Glivec® is a potentially toxic treatment that must be prescribed and consumed under the supervision of an experimented oncologist. Taking a few precautions, most of the patients can continue having a completely normal life. Contrary to what happens with many of the adverse effects of chemotherapy, imatinib’s become more bearable over time.

Fluid retention is the most common adverse effect. As a rule, it occurs in the form of an edema (tender swelling without any redness that leaves a fingermark when pressed) on the eyelids and ankles. If the fluid retention appears in people suffering heart failures or accumulate around the lungs (lung effusion) or the heart (pericardial effusion) it might be dangerous. Fortunately, fluid retention is very easy to detect and treat with diuretic drugs that increase the production of urine.

White and red blood cells and platelets might abnormally drop under the effect of imatinib. If it exceeds certain limit, there will be a risk of infections and severe bleedings. Surely, the oncologist will often perform blood tests at the beginning, leaving longer intervals over time. If the numbers drop, the treatment will be suspended for a few days to allow the patient to recover.

Imatinib might irritate the gastric mucosa, which can be avoided by taking the product along with meals and a lot of water. Feeling ardor or pain in the mouth are important symptoms that should be reported to the oncologist. The patients with a history of stomach or duodenum ulcers must take gastric protectors.

Liver toxicity is the last common adverse effect of the drug. It is usually mild and only detected through a blood test due to an increase in transaminases. It tends to get better by reducing the dose or temporarily interrupting the treatment. People with a prior liver failure or a history of hepatitis should be closely monitored. Other toxicities are very rare and rely on each patients’ individual sensitiveness to the drug. 

What happens when imatinib stops working?

At some point, the disease can escape the treatment’s control and grow again. We do not know If this will happen sooner or later to every GIST patient treated with imatinib.

On the one hand, it is important not to abandon the treatment too soon. In many cancers, the first stage of an answer is a fake increase in the tumor volume. The destruction of the cancer cells releases waste products to the tissues, which triggers a swelling that could be mistaken with a grow in the tumor’ size. Sometimes, this fake increase is the best harbinger of a positive response.

On the other hand, GISTs usually answer to the treatment in a peculiar way, which is different from many other tumors and could be mistaken with a worsening. The center of the tumor devitalizes, turning gelatinous. A previously hard tumor turns into a hollow cavity filled with the remains of the destroyed disease, in which only the wall represents the active stage of the cancer. The size of a living tumor is smaller, even though its real size is the same or even bigger. The vast majority of oncologists are well familiarized with the GISTs’ peculiarities. Still, when facing a precocious progression which is contradicted by an improvement of symptoms, it might be a good idea to ask for a second opinion.

There is also the possibility of a fake progression. Sometimes, most of the patient’s disease is under control but suddenly there is a small portion that starts growing, which is called focal progression. It would be a big mistake to take for granted that imatinib is not working for this patient and suspend it. What is actually happening is that a small portion of the cells have become resistant to the treatment, while the vast majority is still under control. Suspending the treatment would be like opening the prison’s doors just because two prisoners escaped. The only thing we would get would be that the rest of the body immediately followed the path of worsening set by the outpost. If that small area grows it will become removable, so surgery should be considered.

However, there are true progressions in which every infected part of the body gets worse at the same time. This could happen from the very beginning or long after keeping the disease under control with imatinib. A good strategy is to double the doses of the medication, from 400 daily mg to 800. A third part of these patients are able to see how the tumors stop growing again; the stabilization may last for many months.

In case this didn’t work, there is another drug capable of treating GIST. It is called sentinel (Sutent®, Pfizer) and it is also used to treat kidney cancer. Just like imatinib, it is a daily tablet that can be consumed in one or more doses. Although its toxicity is a slightly higher than imatinib, it usually allows to live a normal life. There is no reason to deny sunitinib to a patient once his sickness has progressed, regardless of his age or health state.

Sunitinib’s effectiveness significantly lower than imatinib’s but this may not be because of the drug, but of the development of the disease itself, which usually takes years to evolve when rescue treatment is applied. This treatment is the center of many investigations and studies. For example, it seems that a study about the genetic mutations contained in the malignant cells of GIST could help to predict the sensitivity to the treatments, showing which patients should receive imatinib in the first place, and which ones should try with sunitinib first.

The GIST has gone from being an almost unknown field of Oncology to become one of the most prolific in research. There are a handful of drugs in research, some in very early stages and others closer to commercialization. Currently, almost all the oncologists are familiar with the use of imatinib and sunitinib. However, if the disease worsens despite both, the patient should seek a second opinion from an oncologist specialized in sarcomas, such those who are part of GEIS (a Spanish research group specialized in sarcomas), in pursuit of experimental alternatives.