eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Intestinal Stromal Tumors

Author: Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine
Coauthor(s): Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Contributor Information and Disclosures

Updated: Feb 19, 2010

Introduction

Background

Until 20 years ago, gastrointestinal (GI) mesenchymal tumors were considered smooth muscle sarcomas (leiomyosarcomas). Unlike leiomyosarcomas, however, GI mesenchymal tumors were noted to be highly resistant to chemotherapy. In 1983, Mazur and Clark reported that many of the GI sarcomas lacked the classic immunohistochemical or microscopic evidence of smooth muscle or neural tumors. Therefore, Mazur and Clark coined the term gastric stromal tumor to define these tumors.1 Gradually, these GI mesenchymal tumors came to be known as gastrointestinal stromal tumors (GISTs). GISTs were defined by neoplasms showing incomplete or absent myogenic or neural pathology. An example of a GIST is shown in the image below:


Gastric stromal tumor: Gross specimen following p...

Gastric stromal tumor: Gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration. Image courtesy of Michael Choti, MD.

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Gastric stromal tumor: Gross specimen following p...

Gastric stromal tumor: Gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration. Image courtesy of Michael Choti, MD.


GISTs are now widely believed to originate from, or to be closely related to, the interstitial cells of Cajal. Immunohistochemistry studies comparing GIST cells and the interstitial cells of Cajal strongly support the important roles the cells play in pacemaker activity and motility of the GI tract. Both are positive for CD34, c-kit, and negative for S-100 and desmin.2

GISTs are rare; they constitute only approximately 1% of all GI malignancies. GISTs can develop in any part of the GI tract, from the esophagus to the anus, but primarily occur in the stomach. They may be detected at any size, from less than 1 cm to larger than 30 cm; therefore, their diagnosis and management can be highly variable.

Pathophysiology

GISTs occur in the submucosa, muscularis propria, or the serosa. On gross pathology, GISTs can vary in size, typically ranging from 2 cm to more than 20 cm. Large tumors may have components of necrosis, focal hemorrhage, cystic degeneration, and invasion into adjacent tissues and organs. These tumors are unencapsulated but well circumscribed. More than 50% of GISTs contain a pseudocapsule. Symptoms from GISTs (eg, anemia, intra-abdominal bleeding)are secondary to mass effect or bleeding from the tumors.

Somatic mutations underlie the oncogenesis of nearly all GISTs. Very rarely, familial disorders associated with underlying mutations of the KIT protein result in GIST oncogenesis. People with familial disorders often present with multiple GISTs. Typically, people with multiple GISTs may have associated cutaneous hyperpigmentation, systemic mast cell disease, urticaria, and spindle cell hyperplasia of the GI tract. They all carry a germline mutation of the c-kit proto-oncogene. GISTs can also be a component of Carney triad, a condition without a known mechanism that primarily affects young women. Carney triad is marked by gastric stromal sarcoma, extra-adrenal paraganglioma, and pulmonary chondroma.3 A relationship between neurofibromatosis I and GISTs has also been postulated.4

Mechanism of oncogenesis

The hallmark of GIST oncogenic potential is the constitutive activation of the KIT signaling pathway.5 KIT is a member of the receptor tyrosine kinase family of proteins, a transmembrane protein encoded by the c-kit proto-oncogene. Upon binding its ligand, SCF, homodimerization that leads to autophosphorylation of intracellular tyrosine residues activates the KIT receptor. The activated KIT now functions as a kinase that phosphorylates other kinases such as MAP kinase, PI3 kinases, STAT, and JAK. These proteins are implicated in signaling cascades that induce mitogenesis and differentiation.

In addition to the interstitial cells of Cajal, KIT receptor is expressed in mast cells, melanocytes, Leydig cells, hematopoietic stem cells, cutaneous basal cells, and breast epithelial cells. Nearly all GISTs have mutations of the kit gene that lead to the expression of a constitutively active form of the KIT receptor. Unlike the normal form, mutated KIT does not require binding to its ligand to become active. This shifts the balance between proliferation and apoptosis.

Approximately 90% of metastatic GISTs have been reported to have mutations of the KIT protein, and more than 80% of morphologically benign GISTs also harbor KIT mutations.6 Studies suggest that mutagenesis of the kit gene is an early event in the development of GISTs. Leiomyomas and leiomyosarcomas do not have KIT mutations. Families with germline KIT mutations have multiple GISTs that present at an early age, which also supports the idea that KIT mutation is an early oncogenic event in GIST development. Familial predisposition to GIST formation has been associated with mutation in the PDGFRA gene.7,8

Mutations in BRAF represent an alternative molecular pathway in the early GIST tumorigenesis. Initial studies suggest that GISTs from BRAF mutations have a predilection for the small bowel and are not associated with a high risk of malignancy.9 Mutations of the NF2 gene have also been reported in GISTs, but these mutations do not seem to be an integral part of GIST pathogenesis.10

Frequency

United States

GISTs are relatively rare among the many types of GI tumors. They comprise 5% of all sarcomas and are the largest subset group of mesenchymal tumors of the GI tract. About 60% of GISTs occur in the stomach, 20-30% occur in the small intestine, and 10% occur in other parts of the GI tract. GISTs of the colon, rectum, and esophagus are rare. The distribution of GISTs within the GI tract is as follows11 :

  • Stomach - 60%
    • Cardia and fundus - 15%
    • Body - 70%
    • Antrum - 15%
  • Small intestine - 30%
    • Duodenum - 25%
    • Jejunum - 50%
    • Ileum - 25%
  • Colon - Less than 5%
  • Anorectum - Less than 5%
  • Esophagus - 3%
  • Mesentery, omentum, retroperitoneum - less than 5%
The annual incidence of GISTs in the United States is 200-500 cases. GISTs account for 0.1-2% of all gastrointestinal neoplasms: 3-4% of gastric tumors, approximately 20% of small bowel neoplasms, and 5-10% of all sarcomas.

Mortality/Morbidity

In general, the 5-year survival rate after complete resection is estimated at 50-60% (see Table 1). Most recurrences occur within 5 years of primary diagnosis, though metastases have been reported 10 years postdiagnosis.

In people with GISTs, the disease-specific 5-year survival rate is 30-60%. For primary disease, the median disease-specific survival is 5 years. For people with metastatic cancer, the median survival is approximately 20 months. For people with local recurrence, the estimated median survival is 9-12 months.

Table 1. Survival in patients undergoing resection of GIST12,13,14,15,16

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Table
ReferencePeriodPatients, No.Complete Resections, No.5-y Survival Rate After Complete Resection, %
DeMatteo et al1982-19982008054
Ng et al1957-19971919948
McGrath et al1951-1984513063
Shiu et al1949-1973382065
Akwari et al1950-19741085250
ReferencePeriodPatients, No.Complete Resections, No.5-y Survival Rate After Complete Resection, %
DeMatteo et al1982-19982008054
Ng et al1957-19971919948
McGrath et al1951-1984513063
Shiu et al1949-1973382065
Akwari et al1950-19741085250

The degree of mitosis on histology predicts mortality.11,17 In one review of 55 patients who had surgery with curative intent, the 8-year disease-free survival rate was 80% when the mitosis rate was less than 10 per high power field (HPF), compared with 18-month median survival in people with higher mitotic rates.18

Race

No racial predilection exists.

Sex

No significant sex difference exists.

Age

GISTs primarily occur in middle-aged and older persons, with a median age of approximately 60 years. GISTs rarely occur in people younger than 40 years.

Clinical

History

GISTs are usually asymptomatic until they manifest with symptoms related to their size. Large GISTs cause luminal obstruction or compression of adjacent structures, or hemorrhage may occur within the tumor. Population-based studies suggest that about 70% of patients with GIST present with symptoms, about 20% are asymptomatic on presentation, and the rest of cases are detected on autopsy.

The most common presenting symptoms are vague abdominal pain or discomfort; nausea and vomiting; abdominal mass; abdominal fullness; and secondary symptoms related to bleeding, such as hematemesis, hematochezia, melena, and resulting anemia. Other presenting symptoms are altered bowel function, bowel obstruction or perforation, fever, and dysphagia. GISTs are often discovered during emergency abdominal surgery for bowel perforation or intra-abdominal bleeding. Approximately 50% of GISTs have a metastatic component at the time of presentation, typically involving the liver or the peritoneum.

Typically, small GISTs (approximately 2 cm) do not cause any symptoms. They are often discovered incidentally on screening studies or investigations for other reasons. Typically, they are discovered on endoscopy, abdominal or pelvic CT scanning, and incidentally during intra-abdominal operations. The most common presenting symptom is bleeding (40-50%), followed by bowel obstruction (especially in small bowel GIST).

Physical

People with GISTs can have positive exam findings based on the tumor size and its malignancy status. Findings can include a palpable abdominal mass, abdominal distention secondary to bowel obstruction, and bloody stool on rectal exam.

Causes

Somatic mutations underlie the oncogenesis of nearly all GISTs. Very rarely, familial disorders associated with underlying mutations of the KIT protein result in GIST oncogenesis (see Pathophysiology).

More on Intestinal Stromal Tumors

Overview: Intestinal Stromal Tumors
Differential Diagnoses & Workup: Intestinal Stromal Tumors
Treatment & Medication: Intestinal Stromal Tumors
Follow-up: Intestinal Stromal Tumors
Multimedia: Intestinal Stromal Tumors
References
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References

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Further Reading

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Keywords

GIST, IST, GISTs, gastrointestinal stromal tumors, gastrointestinal mesenchymal tumors, GI mesenchymal tumors, gastrointestinal tumors, GI tumors, leiomyosarcoma, intestinal stromal tumors, interstitial cells of Cajal, GI tract, gastrointestinal malignancies, GI malignancies, gastric stromal tumors, gastrointestinal cancer, GI cancer, stomach cancer, stomach malignancy, stomach tumor, Carney triad, gastric stromal sarcoma, extra-adrenal paraganglioma, pulmonary chondroma, neurofibromatosis I

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Contributor Information and Disclosures

Author

Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine
Matthew Hueman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology
Disclosure: Nothing to disclose.

Coauthor(s)

Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Michael A Choti, MD, MBA is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American Surgical Association, Association for Academic Surgery, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, and Society of University Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: No financial interests None None

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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