Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Gastrointestinal Stromal Tumors is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • GIST

Disorder Subdivisions

  • None

General Discussion

Gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. The number of new cases in the United States annually has been estimated to be 5,000-6,000. Tumors usually arise from the intestinal tract with the most common site being the stomach, followed by the small intestine, and the colon/rectum with rare cases arising in the esophagus. There are also tumors that appear to arise in the membranous tissue lining the wall of the stomach (peritoneum) or in a fold of such membranous tissue (the omentum). There are also case reports of tumors arising in the appendix and/or pancreas. These tumors most commonly present with abdominal pain, bleeding or signs of intestinal obstruction. They spread most commonly to sites within the abdominal cavity and to the liver, although there are rare cases of spread to the lungs and bone. GIST results from a change in one of two genes, KIT or PDGFR, which leads to continued growth and division of tumor cells. There are a few reported cases of families in which a gene mutation is inherited; however, the majority of tumors are sporadic and not inherited.



Treatment is with surgery. Patients who have disease that has spread are treated with surgery when possible and with imatinib mesylate (Gleevec, Glivec), a tyrosine kinase inhibitor that inhibits the KIT or PDGFR responsible for tumor growth. Ongoing studies are testing to see if imatinib mesylate can delay or prevent recurrence of GIST after the tumor has been removed (resection). Standard chemotherapy is not effective for this type of sarcoma, with a less than 5% response rate. The role of imatinib mesylate in pediatric GIST is being studied at this time.

Symptoms

The most common site of origin is in the stomach (39-70%), presenting with pain, GI bleeding and/or a mass that can be seen or felt (palpable). Other primary sites are the small intestine (31-45%), colon and rectum (10-16%), and mesentery (membranous folds that attach various organs to the body wall) or membranous lining of the abdomen (peritoneum) (8%). Patients presenting with tumors of the small intestine may also experience weight loss, fever, abscess, and/or urinary symptoms. There are rare cases presenting in the lowest third of the esophagus causing difficulty with swallowing and weight loss. The primary site of the tumor may be a prognostic factor with small intestinal GISTs having a poorer survival than those originating in the stomach. In addition, intestinal location has been correlated with a high risk of spread (metastases). GIST tumors can also arise in the omentum and mesentery, not in association with a component of the gastrointestinal tract. Tumors present as large masses; some appear to develop in association with cysts. Although the tumors may be large, median survival for this group exceeds two years without any tumor-related deaths. In contrast, the mesenteric GIST primaries appear to behave more aggressively.

Causes

There is no exposure or infection that is known to predispose to GIST. It is known that the majority of tumors will have mutations in the KIT gene, and a minority, in the PDGFR gene. There are common sites for mutations. For the KIT gene, the most common mutation site is in exon 11, but can also involve exon 9, 13, and 17. Mutations in the PDGFR gene involve exon 12 or 18. Exon refers to the region of a gene that contains the code for producing the gene's protein. Each of these mutations is on the long arm of chromosome 4 (4q12).



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4q12" refers to band 12 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



A few families with inherited mutations of the KIT gene have been described. They have early onset of GIST in adolescence or young adulthood. Some families have altered skin pigmentation. In addition, there is a syndrome known as Carney's triad that is associated with GIST tumors, as well as extra-adrenal paraganglioma and pulmonary chondroma. These patients may have a better prognosis, but do not appear to have an underlying KIT mutation.

Affected Populations

The typical patient with a GIST presents in the fifth to seventh decade of life, with some studies suggesting a male predominance. Children have also been found to present with GIST. The disease in children may have a slower time course. There does not appear to be a link to a particular ethnic background.

Standard Therapies

Diagnosis

Diagnosis can be by biopsy. Some tumors are diagnosed by endoscopy. The use of endoscopic ultrasound for lesions in the stomach can be helpful as these tumors can be below the surface of the stomach. If tumors are larger than 2-3 cm, a biopsy suggesting a benign lesion should be interpreted with caution.



Most patients undergo CT scans to determine the extent of the tumor involved. It is most important to image the abdomen and pelvis as the most common sites of spread are within the abdominal cavity and the liver. If patients complain of bone pain, a bone scan should be considered, to determine if there is disease in the bones. PET scanning has been shown to be a helpful additional test; however, at this time it is not routinely covered by insurance companies.



Treatment

Tumors that are confined to one site without evidence of spread are treated by surgical removal. There is no clear benefit for radiation therapy after surgery for this type of sarcoma. Surgery can cure patients if the tumor is completely removed.



Standard chemotherapies have minimal efficacy in patients with GIST that has spread from the original tumor site. Imatinib mesylate, as described above, has been found to be very effective in controlling disease that has spread. The majority of patients will have their tumors decrease in size or stabilize for many months. Although imatinib mesylate has been very effective at controlling disease, patients who have disease that has spread from the initial site (metastatic disease) rarely experience the complete disappearance of all disease. Increasingly, surgery is being combined with imatinib mesylate to control metastatic disease.



Gleevec (also known as imatinib) by Novartis Pharmaceuticals Corporation was granted accelerated approval by the FDA for the treatment of advanced or metastatic GIST in 2002. Imatinib is an oral drug that inhibits the function of both KIT and PDGFR proteins. It has been shown to have significant activity in patients with recurrent tumors



A subsequent accelerated approval was received in 2008 for adjuvant use by patients with GIST who had had potentially curative resection (surgical removal) of GIST tumors, but who were at increased risk for a recurrence. This accelerated approval program provided earlier patient access to Gleevec while the confirmatory clinical trials were being conducted. In 2008, regular approval for the metastatic GIST indication was also granted.



Gleevec was granted regular approval by the FDA in 2012 as a treatment for use in adult patients following surgical removal of CD117-positive gastrointestinal stromal tumors. There is an increase in overall patient survival when the drug is taken for 36 months rather than the standard 12 months of treatment.



Alternative approaches include treatments directed at sites of liver involvement. Embolization or chemoembolization are ways of decreasing blood supply to the tumor sites within the liver and can control disease for some time. Another approach called radiofrequency ablation uses localized radiation; this overcomes the problem of side effects from treating the whole liver with radiation, as normal liver is very sensitive to radiation.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Raghaven D, Brecher ML, Johnson DH. Textbook of Uncommon Cancer. 2nd ed. John Wiley & Sons. New York, NY; 1999:382-84, 433-434.



JOURNAL ARTICLES

Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813-25.



Tosoni A, Nicolardi L, Brandes AA. Current clinical management of gastrointestinal stromal tumors. Expert Rev Anticancer Ther. 2004;4:595-605.



Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol. 2004;11:465-75.



Sattler M, Salgia R. Targeting c-Kit mutations: basic science to novel therapies. Leuk Res. 2004;28 Suppl 1:S11-20.



Eisenberg BL. Imatinib mesylate: a molecularly targeted therapy for gastrointestinal stromal tumors. Oncol (Huntingt). 2003;17:1615-20.



Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg. 2003;90:1178-86.



Wilkinson MD, Fulham MJ. FDG PET imaging of metastatic gastrointestinal stromal tumor. Clin Nucl Med. 2003;28:780-81.



FROM THE INTERNET

How Are Gastrointestinal Stromal Tumors Diagnosed? American Cancer Society. Revised 11/4/2004. 5pp.

wwwcancer.org/docroot/CRI/content/CRI_2_4_3x_How_Are_Gastrointestinal_Stromal



Treatment of GIST Metastases. American Cancer Society. Revised: 11/4/2004. 1p.

www.cancer.org/docroot/CRI/content/CRI_2_4_4x_Treatment_of_GIST_Metastases.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Gastrointestinal Stromal Tumor; GIST. Entry Number; 606764: Last Edit Date; 11/17/2003.

Resources

American Cancer Society, Inc.

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OncoLink: The University of Pennsylvania Cancer Center Resource

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Sarcoma Foundation of America

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Tel: (301)253-8687

Fax: (301)253-8690

Email: info@curesarcoma.org

Internet: http://www.curesarcoma.org



Sarcoma Alliance

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Tel: (415)381-7236

Fax: (415)381-7235

Email: info@sarcomaalliance.org

Internet: http://www.sarcomaalliance.org



Rare Cancer Alliance

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Internet: http://www.rare-cancer.org



Life Raft Group

155 Route 46 West, Suite 202

Wayne, NJ 07470

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Tel: (972)837-9092

Fax: (973)837-9095

Email: LifeRaft@liferaftgroup.org

Internet: http://www.LifeRaftGroup.org



GIST Cancer Research Fund

55 Saw Mill Road

New City, NY 10956

USA

Tel: (845)634-6060

Fax: (845)634-1174

Email: tania5kids@aol.com

Internet: http://www.gistinfo.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



GIST Support International

12 Bomaca Drive

Doylestown, PA 18901

Tel: (215)340-9374

Fax: (215)340-1630

Email: gsi@gistsupport.org

Internet: http://www.gistsupport.org



Friends of Cancer Research

1800 M Street NW

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Tel: (202)944-6700

Email: info@focr.org

Internet: http://www.focr.org



Cancer.Net

American Society of Clinical Oncology

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Tel: (571)483-1780

Fax: (571)366-9537

Tel: (888)651-3038

Email: contactus@cancer.net

Internet: http://www.cancer.net/



Cancer Support Community

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Tel: (202)659-9709

Fax: (202)974-7999

Tel: (888)793-9355

Internet: http://www.cancersupportcommunity.org/



Lance Armstrong Foundation

2201 E. Sixth Street

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Tel: (512)236-8820

Fax: (512)236-8482

Tel: (877)236-8820

Email: media@livestrong.org

Internet: http://www.livestrong.org



BeatSarcoma

76 Ellsworth Street

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Tel: (415)826-0474

Email: info@beatsarcoma.org

Internet: http://www.beatsarcoma.org/



Northwest Sarcoma Foundation

P.O. Box 91460

Portland, OR 97291

Tel: (503)954-5740

Email: melissa@nwsarcoma.org

Internet: http://www.nwsarcoma.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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