Intestinal Stromal Tumors

Updated: Apr 28, 2015
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
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Overview

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 pa 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.

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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 un-encapsulated 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.

Alternative mechanisms of mutagenesis also exist for intestinal GISTs. About 3-5% of KIT -negative GISTs contain PDGFR-alpha mutations. [1, 2, 3] The PDGFR-alpha mutation seems to leave the PDGFR a-receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor. 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 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]

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Epidemiology

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 follows [11] :

  • Stomach - 60% (of these, 15% occur in the cardia and fundus, 70% in the body, and 15% in the antrum)
  • 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 GISTs [12, 13, 14, 15, 16, 17] (Open Table in a new window)

Reference Period Patients, No. Complete Resections, No. 5-y Survival Rate After Complete Resection, %
Caterino et al 1999-2009 47 46 65
DeMatteo et al 1982-1998 200 80 54
Ng et al 1957-1997 191 99 48
McGrath et al 1951-1984 51 30 63
Shiu et al 1949-1973 38 20 65
Akwari et al 1950-1974 108 52 50

The degree of mitosis on histology predicts mortality. [11, 18] 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.

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