Although GIST is often spoken of in the singular, it is actually a family of cancers that encompasses an “adult” form, a “pediatric” form, and several familial (inherited) forms. It is estimated that between 3,000-5,000 people each year develop GISTs in the United States. Although many mutation types have been discovered such as KIT, PDGFRA, SDH and NF1, some forms of the disease still have no known mutation. These are classified into a catch-all category termed “wildtype”. As science advances, we expect these unknown forms will likely be identified. However, regardless of the type of GIST a patient has, learning as much as they can about it is essential.
Understanding GIST Sections:
Gastrointestinal stromal tumors (GISTs) belong to a group of cancers called soft tissue sarcomas. Sarcomas are a rare type of cancer that can occur in connective or supportive tissues. Sarcomas are derived from the general class of cells known as “mesenchymal cells”, found in bone, muscle, fat or cartilage. In contrast, most of the “common” cancers, such as lung, skin, and prostate are derived from “epithelial cells” which are found on the lining of the body’s many surfaces. Cancers that arise from epithelial cells are called carcinomas.
Why does this distinction matter? Carcinomas and sarcomas behave very differently and are treated differently as well. Sarcomas are far less common than carcinomas. Thus, there are fewer oncologists who specialize in their treatment.
GISTs may arise anywhere in the digestive tract. The most common sites are the stomach (40-70%), the small intestine (20-40%), and the colon and rectum (5-15%). GISTs can also be found in the esophagus (<5%). Although very rare, GISTs can develop outside the intestinal tract in the abdominal cavity, these are called eGISTs.
At the time of diagnosis most GISTs (80-85%) are limited to a single site. However, as the disease progresses it is possible for GIST to spread from the original (primary) site to distant locations. If this happens, these secondary tumors are called metastases (or simply, “mets”). It is less common (15-20%) for patients to be metastatic at diagnosis. If GIST tumors do metastasize they usually travel to the liver, or the peritoneum. Metastases to the lymph-nodes and lungs are rare, but do also occur. It is important to understand that when GIST spreads to the liver, for example, those tumors found on the liver are still GISTs, not liver cancer. GIST metastases in the liver are derived from GIST cells and must be treated like GIST cells. Liver cancer is a completely different cancer that starts in the liver.
Discovery of GIST is difficult- GIST tumors can grow quite large before they are found and primary tumors often produce few symptoms. GISTs are often spotted during emergency surgery brought about by unexpected perforation of the gastrointestinal tract and consequent bleeding. When GIST tumors are first discovered, the most common symptoms are:
- Vague abdominal discomfort or pain.
- Presence of a palpable abdominal mass.
- Feeling of abdominal fullness.
- Secondary symptoms resulting from tumor bleeding and associated anemia.
A Brief History of GIST Cancer:
Although the term “GIST” was first used in 1983 (by Mazur and Clark), the 1998 discovery by Hirota that GIST tumors can contain mutations in the KIT gene marked the beginning of a new understanding and reclassification of sarcomas of the Gastrointestinal (GI) tract. Prior to the year 2000, GISTs were previously misclassified as one of many types of soft tissue sarcoma (STS) including tumors of smooth-muscle origin (most commonly leiomyosarcoma, and also leiomyoma or leiomyoblastoma) and those of neural-crest origin (eg, schwannoma, or nerve sheath tumor). Most tumors previously diagnosed as Gastrointestinal Autonomic Nerve Tumors (GANTs) are also now classified as GISTs and contain essentially the identical KIT mutations as GIST. What establishes GIST as a separate diagnosis from these other soft tissue sarcomas is not only the description of where the tumor is located, but also the presence of c-KIT (CD117). It is important to note that there are a small percentage of GISTs which are c-KIT-negative. Most GIST patients are also CD34 positive, DOG1 positive and desmin negative.
KIT-positive? Desmin-negative? What does that mean?
One of the best ways to identify the cancer cell type (aside from just looking at the cells under a microscope) is to determine the proteins that the cell makes. Specialized tests allow the pathologist to do this, usually by determining whether the cell will bind antibodies against the protein of interest. So, “c-KIT-positive” and “DOG1 positive” means that the cell makes the protein “KIT” or “DOG1”, respectively. Desmin-negative means that the cell does not make the protein “desmin”. Testing of these factors are typically done on tissue samples from a biopsy or surgery and the results can be found on a pathology report.
With the development of new effective therapies for GIST, it is vitally important that patients with soft tissue sarcomas of the GI tract have their tumor slides tested for cKIT (CD117) by a pathologist experienced with GIST and KIT. PThose who test as c-KIT-negative, should have DOG1 (Discovered on GIST) IHC staining completed to aid with the diagnosis of GIST.
GISTs were previously thought to arise from smooth muscle cells of the GI tract. The discovery that GISTs express (make) the KIT protein helped establish that GISTs do not originate from smooth muscle. Research has found that GIST tumors arise from the Interstitial Cell of Cajal (ICCs), named for the noted Spanish biologist and microscopist, Santiago Ramon y Cajal. They serve as the pacemaker cells, stimulating movement (contractions) of the GI tract. These contractions, known as peristalsis, force digested food through the gut.
Life Fest 2012 – GIST: From Pathology Puzzle to Targeted Therapy
GIST Cancer Research Is Continually Changing:
GIST research and even GIST clinical practice is advancing quickly. The information presented on this website is accurate at the time of posting but may not capture all changes to the GIST landscape since. Please also note our authors are not medical professionals and the information presented should not be used as a substitute for consultation with a doctor that is experienced with GIST.
No one can take the place of an experienced GIST team of doctors. This may include a Pathologist, Oncologist, and a Surgeon. GIST is such a rare type of cancer that few doctors have much experience in treating it. The hospitals with top sarcoma treatment centers are likely to have more experience with GIST. They have seen many more GIST patients and are more familiar with their unique needs of GIST patients, including treatment options and managing side effects.
The Impact of Targeted Therapy:
The introduction of the drug Gleevec in 2001 as a treatment for GIST was groundbreaking . Gleevec is a molecularly targeted drug that is both more effective and has fewer side effects than traditional chemotherapy. It is currently the first-line therapy for GIST. In February of 2016, the exclusivity patent expired on Gleevec, and the generic form (imatinib) became available for purchase in the United States
Sutent, the second line therapy, is another targeted therapy that was approved in 2006 for GIST that is resistant to Gleevec or for patients who cannot tolerate Gleevec.
Stivarga, the third-line therapy, was approved on February 25th, 2013 in the United States for GIST.
Together, Gleevec, Sutent and Stivarga represent the main drug therapies for advanced GIST. If a patient develops resistance to these, off-labels drugs or drugs in clinical trials may be considered for treatment.