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Gastrointestinal stromal tumours (GISTs) – 2014

UPDATED NOVEMBER 2014

1. GENERAL INFORMATION

1.1 What is the disease and how is it treated?

What are the causes of gastrointestinal stromal tumours (GISTs)?
The causes of gastrointestinal stromal tumours (GISTs) are unknown. The onset is likely connected to a specific alteration in the DNA which involves the constant activation of an enzyme, a receptor called KIT. The KIT receptor (also known as CD117) is a member of the tyrosine kinase family and is responsible for sending signals for growth and survival from the membrane to the cell interior. If the KIT receptor is activated, the cell remains alive and grows or proliferates, even when it normally would not. Another mutation related with tyrosine kinase is in the PDGFRA gene (and consequently PDGF receptor).
These mutations are held to be crucial, early pathogenetic events for these tumours, though further cytogenetic alterations are probably required to give rise to clinically relevant GISTs.
There are also a number of hereditary conditions related to specific DNA mutations which generally result in the development of multiple GISTs, diagnosed at an earlier than average age (Neurofibromatosis, Carney triad and Carney-Stratakis syndrome, Germline KIT- and PDGFRA-mutated GIST).

What organs are most affected?
About 60% of GISTs develops in the stomach, 30% in the small bowel, 5%-10% in the rectum (rarely the colon), less than 5% in the oesophagus. At times, GISTs develop outside of the intestinal tract, although still in the abdomen.

Is it a frequent type of cancer?
Gastrointestinal stromal tumours (GISTs) are rare tumours. It is estimated that each year about 1.5/100,000 people develop a GIST. These estimates do not include small GISTs incidentally found during diagnostic or therapeutic procedures carried out for other reasons. In most cases, these small GISTs are clinically insignificant.

How is it treated?
Surgery is the treatment mainstay for localized disease, when complete excision of the primary tumour is feasible and the disease has not spread elsewhere. The goal of surgery is complete removal of all visible tumour.
Medical therapy is promising. Imatinib specifically blocks the altered KIT enzyme, which is involved in uncontrolled growth of cancer cells, and the PDGF receptor, another enzyme that can be linked, in some cases, to the proliferation of GISTs. Therapy with Imatinib is called “molecular targeted therapy” because its action, like the action of other similar new drugs, is specific to molecular targets that are very important for cancer cell proliferation.

2. GASTROINTESTINAL STROMAL TUMOURS (GISTs): WHAT ARE THEY, HOW DO THEY OCCUR, HOW ARE THEY DIAGNOSED?

2.1 What are gastrointestinal stromal tumours (GISTs)?

Gastrointestinal stromal tumours (GISTs) form when cells of the gastrointestinal tract multiply abnormally, out of control. The gastrointestinal tract is part of the digestive system, and it performs the following functions:
• intake of food;
• digestion and absorption;
• elimination.
It is a continuous tube, about 11 metres long in adult humans, and it includes, from top to bottom: oesophagus, stomach, small bowel, and large bowel.
Gastrointestinal stromal tumours (GISTs) are classified as soft tissue sarcomas. Sarcomas are rare tumours whose cells resemble those that give rise to connective tissue (muscle, fat, blood vessel walls, cartilage and bone). GISTs are essentially sarcomas that originate in the digestive tract, from the oesophagus to the anus. In particular, the tumour cells show similarities with special cells called “interstitial cells of Cajal” which have characteristics intermediate between those of nerve cells and muscle cells, and coordinate the automatic contractions of the gastrointestinal tract wall.

2.1.1 Why they develop and grow

The causes of GISTs are unknown. The out-of-control growth of the cells, which is the basis of tumour formation, is likely connected to a specific DNA alteration in the KIT gene, which involves the constant activation of an enzyme, a receptor called KIT. The KIT receptor (also known as CD117) belongs to the tyrosine kinase family and is responsible for sending signals for growth and survival from the membrane to the cell interior. If it is activated, the cell remains alive and grows or proliferates, even when it normally would not. Thanks to the understanding of the mechanism of tumour transformation, new targeted molecular therapies for this cancer have been found, which act directly on the altered enzyme by “turning off” the activity and blocking uncontrolled cell proliferation. Another mutation related with tyrosine kinase is in the PDGFRA gene (and consequently PDGF receptor).These mutations are held to be crucial, early pathogenetic events for these tumours, though further cytogenetic alterations are probably required to give rise to “malignant”, clinically relevant GISTs.
There are also a number of hereditary conditions related to specific DNA mutations which generally result in the development of multiple GISTs, diagnosed at an earlier than average age (Neurofibromatosis, Carney triad and Carney-Stratakis syndrome, Germline KIT- and PDGFRA-mutated GIST).

2.1.2 Disease stats

How many people become ill with gastrointestinal stromal tumours (GISTs)?
GISTs are rare tumours. Even though the incidence of the disease is not yet fully known, it is estimated that about 1.5/100,000 people develop a GIST each year. These estimates do not include small GISTs incidentally found during diagnostic or therapeutic procedures carried out for other reasons. In most cases, these small GISTs are clinically insignificant.
Are there any sex- or age-related differences in the frequency of this cancer?
There is a moderate male predominance, around 1.5 men for each woman (1.5:1). Median age is around 60 years. More frequent, typical GISTs (with mutations of the KIT or PDGFRA gene) occur in adults, with a sharp increase as age progresses. Age distribution, however, is wide, and all ages can be affected. Paediatric GISTs are rare, marked by gastric origin, frequent multifocality, slow growth, nodal metastases, and they occur mainly in females. Paediatric-type GISTs may also occur in adults.

2.2 Risk factors

Some people are at higher risk than others of developing certain diseases. This can be due to different risk factors. A risk factor is something that increases the chances of a person to contract a disease like cancer; however, a person who has one or more risk factors will not necessarily get sick.
In particular, there are no specific risk factors for gastrointestinal stromal tumours: only rarely, GISTs develop in the presence of conditions that may predispose a person to get sick. One of these predisposing conditions is a very rare family syndrome, called Neurofibromatosis type I. In most cases, both predisposing factors and causes of the disease are unknown.

2.3 What are the symptoms of gastrointestinal stromal tumours (GISTs)?

GISTs are rare and early diagnosis is difficult. They tend to grow outwards from within the gastrointestinal wall, giving rise to often symptomless abdominal masses. Mucosa may long be spared, and this may prevent early clinical signs such as minor gastrointestinal bleeding. Endoscopic recognition of the disease can be difficult as well, though some early or low-risk cases can be detected this way. Diagnosis is often made at an advanced stage, on radiological recognition of an abdominal mass, or on an emergency basis, because of the sudden onset of gastrointestinal or peritoneal bleeding. No serous marker is available. For all these reasons, screening is not possible, and it is difficult to identify preclinical cases.
GISTs can present different signs and symptoms.

  • A mass in the abdomen, which can become palpable or visible. In fact, many GISTs are diagnosed because an abnormal abdominal mass is found on examination or palpation, which can also be detected by diagnostic tests performed for other reasons. If the abdominal mass is large, it can give rise to abdominal symptoms, such as pain or intestinal disorders, sometimes vague, sometimes connected to the compression of the neighbouring organs.
  • Gastrointestinal (from the mouth or the rectum) or peritoneal bleeding: in some cases GISTs are diagnosed in a totally unexpected manner, because of bleeding from the mouth or rectum, or the peritoneum. In these cases, an acute condition may develop, requiring emergency surgery.
  • Minor bleeding, which can result in anaemia. However, it is to be noted that in GISTs, even at a relatively early stage, some typical signs of the most common cancers of the gastrointestinal tract, such as, in particular, minor bleeding (faecal occult blood, etc.), are often missing. This is mainly because, at least initially, GISTs arise in the wall of the gastrointestinal tract and not from the mucosa (the innermost layer of the wall).

Finally, there are cases in which the diagnosis of GIST is made incidentally as a result of an examination, for example, an endoscopy, or even surgery, performed for other reasons. Often these are very small GISTs, often at lower risk of severe outcomes.
All GISTs, however, must be carefully considered, because the risk of recurrence is never zero.

2.4 What organs are most affected?

GISTs arise from within the gastrointestinal wall. A few cases might be extragastrointestinal, but occult gastrointestinal disease may be present in these cases, as well. About 60% of GISTs develops in the stomach, 30% in the small bowel, 5%-10% in the rectum (rarely the colon), less than 5% in the oesophagus. Sometimes, GISTs develop outside of the intestinal tract, although still in the abdomen.

2.5 Diagnosis

2.5.1 How is the disease identified as a gastrointestinal stromal tumour (GIST)?

Faced with suspicious symptoms, to make an accurate diagnosis a doctor may use the following diagnostic tests.

  • Ultrasound: a radiological technique that makes it possible to view the internal parts of the body as two-dimensional images, using high-frequency sound waves (ultrasound).
  • CT (Computed Tomography): a radiographic technique that uses a computer to photograph internal parts of the body.
  • MRI (Magnetic Resonance Imaging): magnetic waves detect images of the internal organs of the body.
  • Gastroscopy and / or colonoscopy: exams that make it possible to view the internal walls of the stomach and colon-rectum, respectively, through the introduction of a thin, flexible tube that has a small camera on the top; a biopsy may also be performed by means of this tube.
  • Another possible tool is endoscopic ultrasound: ultrasound of the internal walls of the stomach and colon-rectum, which can be performed during gastroscopy and / or colonoscopy. If one of these tests shows an abdominal mass, to confirm diagnosis the next step is an histological examination, i.e., removal of the tumour tissue (biopsy) and its analysis. A biopsy can be performed during endoscopy, if the mass is accessible from the lumen of the gastrointestinal tract, by introducing through the throat a thin tube with a light on the end of it, or with ultrasound or CT guidance. In other cases, surgical laparotomy is necessary. Diagnosis is made based on the biopsy sample. It is also very important to determine the presence of the KIT enzyme (CD117), which is detected thanks to a particular staining of the tissue samples, called immunohistochemical staining.
2.5.2 Do these tests involve any risks for patients?

Generally, all of these exams are well tolerated. Only endoscopy (gastroscopy and colonoscopy) can cause discomfort. In any case, at the time of referral, patients should receive the necessary information with regards to the various tests they will undergo.

3. HOW ARE GASTROINTESTINAL STROMAL TUMOURS (GISTs) TREATED?

3.1 Referral

GISTs are rare tumours. Thus, they should be referred to centres of expertise where multidisciplinary teams experienced in treating the disease are available. In fact, treatment may be multimodal both in the localized and in the advanced disease setting. If diagnosis is made on an emergency basis, the patient should be referred after surgery. Pathologic diagnosis should be reviewed by an experienced pathologist.

3.2 The first choice: surgery

3.2.1 When is surgery appropriate?

To date, surgery is the main treatment of localized disease. The goal of surgery is the complete removal of all visible tumour. For GISTs with distant metastases, surgery alone is not successful, and in other cases it is not feasible for the extension of the primary tumour. In addition, GISTs are resistant to conventional chemotherapy.

3.2.2 What are the possible side effects of surgery?

The side effects of surgery on the gastrointestinal system depend on the magnitude of the surgery and on which organs the surgeon is able to save, or needs to sacrifice.

3.2.3 What psychological impact can surgery have?

Faced with the news of upcoming surgery patients may:

  • feel that their physical and mental integrity is threatened;
  • be afraid to place their trust in the hands of a stranger;
  • be afraid of the surgery itself and fear damage to their bodies,
  • be worried about separation from family.

When surgery concerns an internal organ, such as in this case, patients may repress certain emotions.
To limit these reactions, it is advisable for patients to express their fears and concerns with their doctor: a good relationship between physician and patient is essential to tackle the disease.

3.3 Drug therapy

3.3.1 A new drug: Imatinib

This drug has been used since 2000-2001, primarily in the treatment of chronic myeloid leukaemia and GISTs. It is taken by mouth and specifically blocks the altered KIT enzyme (which is involved in the uncontrolled growth of cancer cells), and also another tyrosine kinase enzyme, the receptor for PDGF, which in some cases can be linked to GIST proliferation. For this reason, therapy with Imatinib and other similar drugs is called “molecular targeted therapy”: the action of these drugs is specific to molecular targets that are very important for cancer cell proliferation. This involves a therapeutic action that is quite predictable in relation to the presence of the target, and, overall, infrequent side effects. In particular, Imatinib is typically associated with few side effects, namely chiefly water retention, fatigue, muscle cramps, diarrhoea, rash, nausea. In general, these effects resolve spontaneously after a few weeks of therapy, but in some cases they may persist and worsen. Therefore, it is important for treatment with this drug to be followed directly by a medical oncologist. On the other hand, this drug has a high probability of being active in GISTs, around 80% to 90%. In other words, there are relatively few GIST patients that do not respond favourably to therapy.

3.3.2 Other drugs

After months, or even years of treatment with Imatinib, tumours can become resistant to the drug. There are other medications that can be effective in patients resistant to Imatinib. As Imatinib, they act directly on the underlying mechanisms of tumour growth.

3.3.3 Side effects related to drug therapy

Side effects are moderate in most patients. The most common toxic effects are limited to the first period of therapy, for a few days or weeks, and include:

  • water retention, with swelling of the ankles and around the eyes;
  • diarrhoea;
  • rash;
  • asthenia;
  • muscle cramps.

At the beginning of treatment, less than 5% of patients may experience the following:

  • episodes of major bleeding, due to the rapid response of the tumour lesions. In practice, the therapeutic effect may involve a bleeding within the tumour.

Sometimes, this can result in:

  • significant anaemia, which may require immediate transfusions and urgent measures

or

  • bleeding in the gastrointestinal tract (from the mouth or rectum) or within the peritoneum. In these cases, urgent measures, including surgery, may be necessary. These side effects are more common during the first months of treatment.

After a prolonged therapy, the following may appear:

  • a modest myelosuppression, with a reduction in white blood cells and platelets, and, more often, red blood cells (chronic anaemia). Additionally, there may be:
  • liver toxicity (for example, with increased transaminases), which can sometimes compromise the regular administration of the therapy. Patients with liver disease, or at risk for liver disease (hepatitis virus infections) may require special attention by the hepatologist, and possibly also liver specific treatment.

During chronic intake of the drug used for chronic myeloid leukaemia, the appearance of:

  • gynaecomastia has been described, in connection with a reduction in the level of testosterone; sometimes, impotence has been reported in male patients.

3.4 Chemotherapy

3.4.1 When is chemotherapy used?

Conventional chemotherapy, such as that usually employed in soft tissue sarcomas, is not very active in GISTs.

3.4.2 How does chemotherapy work?

Chemotherapy uses drugs to kill cancer cells (anticancer chemotherapeutic drugs), which may be administered by mouth or be injected into the muscle or into the veins. The drugs can be used individually or, more often, in combination. Once in the blood, the drugs are transported throughout the body.

3.5 Radiotherapy

3.5.1 When is radiotherapy used?

Radiotherapy is not generally used, especially due to the site of origin of these tumours, which does not lend itself to radiation treatment. It is not excluded that some cases of GISTs originating in the rectum may benefit from radiotherapy, but, at present, it is not a conventional option. However, stromal tumours of the rectum are rare among GISTs.

4. THE STAGES OF GASTROINTESTINAL STROMAL TUMOURS (GISTs)

The stage of a tumour indicates its extension in the organ of origin and its spread to lymph nodes or other organs (metastasis).

4.1 Staging of gastrointestinal stromal tumours (GISTs)

At the moment, there is no useful stage classification system for GISTs, and it is generally preferred to classify the disease as follows.

  • Localized disease stages: the multiplication of the cells (rate of mitosis), the tumour’s size and primary site are prognostic factors. Some risk assessment systems have been proposed in recent years based on these factors.
  • Disseminated (metastatic) disease stage: GISTs tend to metastasize to the peritoneum and to the liver, so the disease tends to remain confined to the abdomen throughout its natural history. Extra-abdominal metastases may occur in a limited number of patients, mainly in the bones. Supradiaphragmatic nodes and distant soft tissues may, rarely, be affected. Lung lesions are rare, with the exception of rectal GISTs. In other words, GISTs diffuse, recur in, and mainly involve the abdominal area.

5. TREATMENT OF GASTROINTESTINAL STROMAL TUMOURS (GISTs)

5.1 Treatment of localized disease

Surgery is the main course of treatment in the presence of localized resectable disease, i.e., when it is considered possible to completely remove the tumour. Complete resection, without residual disease, is the best treatment for operable disease.
It is currently under investigation whether medical treatment with Imatinib could be helpful to reduce the risk of relapse after surgery, using it in a way that is precautionary, as is done with adjuvant chemotherapy in several other cancers.
To date, this has not been proven, as studies designed to evaluate this hypothesis are still ongoing. At the moment, therefore, use of adjuvant Imatinib outside of clinical trials should be avoided.
Clearly, use of adjuvant Imatinib could prove beneficial, reducing the risk of relapse and thereby increasing the chances of a cure, but it may also increase the risk of acquired resistance by the tumour, at least anticipating resistance compared to a later stage in which use of the drug becomes necessary for a relapse.
Therefore, the adjuvant option should be discussed with the medical oncologist and, if approved, administered in controlled clinical trials. Of course, the option of adjuvant treatment is still to be reserved for patients with a higher risk of relapse, i.e., patients with significant risk factors.

5.2 Treatment of disseminated/metastatic disease

The approach to metastatic disease is based on molecularly targeted therapy with Imatinib. Therapy must be continued indefinitely, since the disease progresses if therapy is stopped, even in cases in which complete radiological remission has been achieved. The limiting factor of Imatinib is secondary resistance, after which alternative drugs can be used, after checking whether there are problems which may diminish the efficacy of the administered dose of the first drug; in any case, an attempt to escalate Imatinib dosage is generally made. In addition, in case of focal progression, surgery of progressing lesions is appropriate. On the contrary, surgery of generalized progression has been shown to be ineffective.
If resorted to, surgery of residual disease during medical therapy with Imatinib should be viewed as a debulking surgery, aimed at excising gross residual disease in an attempt to delay secondary resistance. The efficacy thereof has not been demonstrated.

6. PROGNONIS

6.1 General information

Prognosis indicates the likelihood that the treatment will be successful. It is a statistical data obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics are indicative: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

6.2 The prognosis of gastrointestinal stromal tumours (GISTs)

Regarding GISTs, the main factors involved in prognosis are:

  • the extension of the disease (localized or metastatic),
  • in localized disease: size, rate of mitosis and primary tumour site,
  • in metastatic disease, prognosis has recently improved after the introduction of molecularly targeted therapies.

Data reflect the past, and do not take into account the substantial progress which has occurred in the treatment of GISTs. Five-year survival rates around 60% have been reported for localized, surgically treated disease, while metastatic disease had a bad prognosis before the introduction of molecularly targeted therapies. More recently, the 5-year survival rate has been reported to be close to 50% in studies on metastatic patients treated with Imatinib. Chances of cure in the localized disease setting are highly dependent on some prognostic factors, varying substantially according to mitotic count, tumour size, and tumour site.

7. WHAT TO DO AFTER TREATMENT

7.1 General information

After completing treatment, the oncologist will plan a series of subsequent visits and additional tests to monitor the effects of treatment and make sure that cancer does not recur. It is important for patients to contact their oncologist immediately in case of new symptoms or side effects, even beyond the already scheduled appointments that are part of the planned follow-up care schedule.

7.2 The follow-up of gastrointestinal stromal tumours (GISTs)

  • Localized disease. In roughly 80% of GIST recurrence, patients relapse within 2-3 years from surgery for local disease, although long delayed recurrences are well known. In addition, 95% of recurrences selectively involve one or both the typical sites of relapse in this disease: the peritoneum and liver. Abdominal CT-scan or MRI are thus the options of choice to detect the most frequent recurrences from GISTs. Possibly, they might be alternated with ultrasounds, especially in thin patients. Risk of recurrence is essentially dictated by rate of mitosis, size, and site of origin.
    At least in the first years, regular follow-up with CT scan or MRI at close intervals, possibly alternating with ultrasounds in thin patients, is recommended, especially in high risk patients. Then intervals can be relaxed, but follow-up should be prolonged for several years. A reasonable protocol may include abdominal CT or MRI every 3 months for 2 years from surgery, or the end of adjuvant therapy, then every 6 months for a further 3 years, then yearly.
  • Disseminated disease. GIST patients responding to Imatinib should be watched closely because the risk of secondary resistance increases over time. It is recommended that patients on therapy with Imatinib and other agents be closely followed-up. Generally this happens at approximately 3-month intervals.

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