AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Background

GI stromal tumors (GISTs) are a subset of GI mesenchymal tumors of varying differentiation. Previously, these tumors were classified as GI leiomyomas, leiomyosarcomas, leiomyoblastomas, or schwannomas as a result of their histologic findings and apparent origin in the muscularis propria layer of the intestinal wall. With the advent of immunohistochemical staining techniques and ultrastructural evaluation, GISTs now are recognized as a distinct group of mesenchymal tumors. In the present classification, GISTs account for approximately 80% of GI mesenchymal tumors (Nishida, 2000).

Most tumors described as leiomyomas and leiomyosarcomas in the older medical literature actually refer to GISTs (Miettinen, 2001). Only with tumors in the esophagus does the term leiomyoma remain accurate. Leiomyomas are the most common mesenchymal tumors in the esophagus, and they rarely occur in the stomach and small bowel. In contrast, GISTs are rare in the esophagus, and they are more common in the stomach and small bowel.

The literature about GISTs remains confusing because tumor classification and terminology are continually refined. Furthermore, the exact definition of GISTs varies among authors. Some use the term to describe any GI submucosal mesenchymal tumor that is not myogenic (eg, leiomyosarcoma) or neurogenic (eg, schwannoma) in origin. Others are more restrictive and use the term when specifically referring to GI mesenchymal tumors that express the CD117 and/or CD34 antigen. This review includes material from both points of view.

Pathophysiology

Grossly, GISTs are well-demarcated spherical masses that appear to arise from the muscularis propria layer of the GI wall. Intramural in origin, they often project exophytically and/or intraluminally, and they may have overlying mucosal ulceration. Larger GISTs nearly always outgrow their vascular supply, leading to extensive areas of necrosis and hemorrhage (see Images 1-2) (Pidhorecky, 2000; Miettinen, 2001).

The diameter of GISTs, as a whole, can range from a few millimeters to more than 30 cm. Although larger tumors have a higher rate of malignancy, size does not predict benignity, and small GISTs have been known to behave in a malignant fashion (Pidhorecky, 2000; Lehnert, 1998). Malignancy is characterized by local invasion and metastases, particularly to the liver.

Cytologically, GISTs can be classified into 2 broad categories: spindle cell GISTs and epithelioid GISTs. Spindle cell GISTs are characterized by a nuclear palisading or prominent perinuclear vacuolization pattern. Epithelioid GISTs may have either a solid pattern or a myxoid pattern, with a possible compartmental pattern. Although GISTs can differentiate along either or both cell types, some show no significant differentiation at all (Pidhorecky, 2000; DeMatteo, 2000; Miettinen, 2001).

The number of mitotic figures present can be used to histologically grade GISTs. Unfortunately, no standard exists for their classification. In general, GISTs with less than 1 mitotic figure per 50 high-powered fields (HPFs) are correlated with benign behavior. A finding of 1-5 mitoses per 10 HPFs suggests potential malignancy. A finding of more than 5 per 10 HPFs indicates malignancy. A finding of more than 10 per 10 HPFs denotes high-grade malignancy (Pierie, 2001; Pidhorecky, 2000; Miettinen, 2001).

Although GISTs can be suggested radiologically or histologically, the diagnosis must be made immunochemically. Independent of location, most GISTs express the CD34 antigen (70-78%) and the CD117 (72-94%) antigen. The CD34 protein is a hematopoietic progenitor cell antigen that occurs in a variety of mesenchymal tumors. CD117 also is known as the c-kit protein; it is a membrane receptor with a tyrosine kinase component. Mutations in the CD117 gene have been linked to malignant behavior in GISTs (Miettinen, 2001; Miettinen, 2000; Lasota, 1999; Tazawa, 1999; Pidhorecky, 2000).

As noted previously, some authors specifically use the term GIST to refer to only those mesenchymal tumors that express CD117, whereas others believe that the diagnosis can be made in the absence of CD117 positivity on the basis of clinical and morphologic features (Nishida, 2000; Miettinen, 2001; Berman 2001). Recently, some GISTS without the KIT mutation have been found to express a mutation in another tyrosine kinase receptor gene, the PDGFRa gene. This gene encodes the platelet derived growth factor receptor (alpha receptors) tyrosine kinase protein (Tamborini, 2004; Joensuu, 2004).

Interstitial cells of Cajal are GI pacemaker cells that regulate intestinal motility and peristalsis. A relationship between GISTs and Cajal cells has been proposed, because these are the only 2 intestinal entities to express both CD34 and CD117. Whether GISTs are Cajal cell tumors or whether they share a common progenitor cell is unknown (Sircar, 1999; Nishida, 2000; Miettinen, 2001).

Other markers that have been used in the evaluation of GISTs include desmin, actin, and S100. About 20-30% of GISTs express smooth muscle actin, only 5-10% express desmin, and as many as 10% of GISTs may have positive results with S100 (Miettinen, 2001). In contrast, true leiomyomas and leiomyosarcomas typically have positive results with desmin and actin but negative results with CD34 and CD117, although some leiomyosarcomas may contain isolated CD117 cells. This finding is in contrast to the generally global presence of CD117 in GISTs (Miettinen, 2001). Schwannomas typically have positive results with S100 and negative results with CD34 and CD117 (Miettinen, 2001; Lasota, 1999; Sircar, 1999; Miettinen, 1995).

About 10-30% of GISTs have malignant behavior (Nishida, 2000; Miettinen, 2001). A benign GIST cannot be conclusively diagnosed, because even small, histologically benign-appearing tumors may later demonstrate clinically aggressive behavior. Nonetheless, factors that are correlated with an improved prognosis include a gastric location, a diameter of less than 2 cm, a low mitotic index, and an absence of tumor spillage with complete gross resection.

Major negative prognostic factors include large size (>5 cm), high mitotic index, and grossly positive resection margins. Other factors with poor prognosis include tumor rupture, distal location, high cellularity, tumor necrosis, presence of metastases or invasion, and mutation in the c-kit gene (Tazawa, 1999; Nishida, 2000; DeMatteo, 2000; Miettinen, 2001; Berman, 2001). Findings from 2 studies show that microscopic resection margins are not correlated with improved outcome (Pierie, 2001; DeMatteo, 2000). Given the potential malignant behavior of benign appearing GISTs, at least 1 group believes that all GISTs should be classified as malignant tumors on a low-to-high grading scale rather than on a benign-versus-malignant basis (Pierie, 2001).

GISTs rarely spread to regional lymph nodes ( <10%). Rather, malignancy is manifest by local invasion; distant metastases most commonly involve liver (50-65%) and peritoneum (21-43%) (see Image 3). Only 10% of metastatic lesions occur in the lungs or bones (DeMatteo, 2000; Miettinen, 2001; Lehnert, 1998; Plaat, 2000; Tazawa, 1999; Pierie, 2001).

Frequency

United States

GISTs are rare tumors, constituting less than 3% of all GI malignant neoplasias (Pierie, 2001; Kim, 2001; Pidhorecky, 2000). Specifically, they represent only 20% of small-bowel malignant neoplasms (excluding lymphoma); 1-2% of gastric malignancies; and less than 1% of malignancies involving the esophagus, colon, and rectum (Plaat, 2000; Pidhorecky, 2000; Nishida, 2000; DeMatteo, 2000; Lehnert, 1998). On presentation, 41-47% of malignant GISTs are metastatic (Plaat, 2000; Pierie, 2001; DeMatteo, 2000; Miettinen, 2001).

Mortality/Morbidity

Regardless of the presentation, the disease-specific survival rates with malignant GISTs are 69% at 1 year, 38-44% at 3 years, and 29-35% at 5 years. Benign GISTs were not included in the findings from 2 surgical studies cited. Median disease-specific survival was 60 months with primary disease, 19 months with metastatic disease, and 12 months with local recurrence (DeMatteo, 2000; Pierie, 2001).

In patients who had malignant primary disease and who underwent complete gross resection of the tumor, 40% had recurrence; 91% of the patients died from the disease during the course of 1 study. The disease-specific survival rate in this group of patients was 88% at 1 year, 54-65% at 3 years, and 42-54% at 5 years. Median survival was 66 months in those who underwent complete gross resection of the primary disease and only 22 months in patients with incomplete or nonresectable primary tumors. Recurrence is typical, and the rate has been reported to be as high as 90% at long-term follow-up (DeMatteo, 2000; Pierie, 2001; Pidhorecky, 2000).

Race

No racial predilection exists.

Sex

The occurrence is approximately equal in both sexes. Some studies show a slight preponderance in men (Miettinen, 2001; Lehnert, 1998; Pidhorecky, 2000).

Age

GISTs have a unimodal peak incidence in persons aged 40-70 years, but they have a broad distribution. Very rare pediatric cases have been reported (Miettinen, 2001; Lehnert, 1998; Pidhorecky, 2000).

Anatomy

About 50-70% of GISTs occur in the stomach; 33%, in the small bowel; 5-15%, in the rectocolon; and only 1-5%, in the esophagus (Plaat, 2000; Pidhorecky, 2000; Nishida, 2000; DeMatteo, 2000; Lehnert, 1998; Berman 2001). GISTs are multicentric in fewer than 5% of cases (see Images 5-6) (Nishida, 2000).

Clinical Details

These tumors have a wide clinical spectrum at presentation. They range from incidentally detected, asymptomatic, benign GISTs to large malignant tumors, which frequently cause the patient to seek medical attention (Miettinen, 2001).

If symptomatic, GISTs usually cause symptoms as a result of their size or tendency to ulcerate and bleed. The most common presenting signs and symptoms include abdominal pain, GI bleeding manifested by hematemesis or melena, and a palpable mass. Although these tumors rarely cause obstruction, they can become perforated in as many as 20% of cases. The rare esophageal GIST most often causes symptoms of dysphagia, due to obstruction, and subsequent weight loss (Levine, 1996; Miettinen, 2001; Pierie, 2001; Pidhorecky, 2000; Nishida, 2000; Lehnert, 1998; Miettinen, 2000).

Limitations of Techniques

The aim of radiologic examination is to locate GIST lesions, evaluate local invasion, and detect distant metastases. The radiographic characteristics of GISTs mirror the gross appearance of these tumors. Small GISTs appear as small well-circumscribed intramural masses, possibly with overlying ulceration. Larger malignant GISTs appear as complex masses, with areas of necrosis as the tumor outgrows its blood supply.

Unfortunately, radiologic findings are nonspecific and can represent several entities. Also, the distinction between benign and malignant GISTs cannot be made with radiologic examinations unless metastatic disease or tumor invasion of adjacent structures is depicted. The definitive diagnosis of GIST is made immunohistochemically. However, the diagnosis can be suggested in the case of a complex bowel mass with liver metastases in the absence of lymphadenopathy.

DIFFERENTIALS

Section 3 of 11  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Other Problems to be Considered

Angiosarcoma
Inflammatory fibroid polyp
Inflammatory myofibroblastic tumor (pseudotumor, fibrosarcoma)
Intra-abdominal fibromatosis
Kaposi sarcoma
Lipoma
Lymphoma, abdominal
Melanoma, metastatic
Schwannoma, GI

RADIOGRAPH

Section 4 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Findings

Plain radiographs usually offer little in the evaluation of GISTs. In the chest, esophageal GISTs can appear as a soft tissue mass in the lower two thirds of the mediastinum. In the abdomen, the soft-tissue mass may cause deformation of the gastric air shadow or displace loops of bowel. Abdominal films may depict an obstructive bowel pattern. If necrotic, collections of air can be visualized within the tumor (Shojaku, 1997).

Regardless of the location of GISTs, barium-enhanced images demonstrate predominantly intramural masses with potential exophytic components. The tumor margins usually are smooth, but with ulceration, some surface irregularity is present. As with other intramural masses, the tumor borders form right or obtuse angles with the adjacent visceral wall. En face, the intraluminal surfaces often have well-defined margins (see Images 7-10).

Because the tumors are intramural but extramucosal, the overlying mucosa can be intact. In the stomach, this location results in a preserved areae gastricae pattern over the tumor mass. However, overlying mucosal ulcerations are often present; they are more common in malignant GISTs. These ulcerations fill with barium, causing a bull's eye or target-lesion appearance (see Image 11).

If necrosis and cavitation are present, barium may fill the inner parts of the tumor mass (see Images 12-13) (Levine, 1996; Shojaku, 1997; Ishii, 1997; Pidhorecky, 2000; Lehnert, 1998). At times, the mass is entirely exophytic, and thus, it is not appreciated during contrast-enhanced examination. Barium images outline the intraluminal portion of this tumor; frequently, a substantial exophytic extension is present (see Images 14-15).

Degree of Confidence

One group reported that double-contrast images show abnormalities in 80% of cases (Pidhorecky, 2000).

CT SCAN

Section 5 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Findings

CT should be performed with both oral and intravenous contrast materials. CT is ideal in defining the endoluminal and exophytic extent of tumor. Smaller GISTs appear as smooth, sharply defined intramural masses with homogenous attenuation (see Image 9).

Contrast enhancement may be rimlike or uniform (see Image 15). Occasionally, dense focal calcifications are present. Larger GISTs with necrosis appear as heterogeneous masses with enhancing borders of variable thickness and irregular central areas of fluid, air, or oral contrast attenuation that reflect necrosis (see Image 4, Image 13). Overlying mucosal ulcerations and extension into nearby structures may be present.

CT is also sensitive for the detection of metastatic liver, peritoneal, lung, and bone lesions. The diagnosis of GIST can be suggested in the presence of a large, complex, intestinal mass with liver lesions but without significant lymphadenopathy. Liver lesions can be hypervascular or appear as cystic multilocular lesions with fluid-fluid levels (Levine, 1996; Miettinen, 2001; Shojaku, 1997; Buckley, 1998; Lehnert, 1998; Miettinen, 2000).

Degree of Confidence

CT scanning has good sensitivity for the detection of GISTs, and it can show abnormalities in 87% of cases (Pidhorecky, 2000).

MRI

Section 6 of 11  

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• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Findings

Among imaging studies, MRI has the best tissue contrast, which aids in the identification of masses within the GI tract. Further, the ability to image in multiple planes facilitates localization and diagnosis. Intravenously administered contrast material is needed to evaluate lesion vascularity.

GISTs appear as sharply delineated, heterogeneous masses with cystic and necrotic areas. The masses tend to be isointense relative to skeletal muscle on T1-weighted images and hyperintense on T2-weighted images. Signal intensity voids are present if gas is present within areas of necrotic tumor (Levine, 1996; Shojaku, 1997; Tervahartiala, 1998).

ULTRASOUND

Section 7 of 11  

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• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Findings

If indicated, ultrasonography is ideal for guided needle biopsy of known lesions. With immunohistochemical staining methods, the diagnosis can be made prior to surgery (Seidal, 2000). However, aspiration (eg, fine-needle aspiration) and biopsy should be used selectively because of the risk of tumor seeding or peritoneal spillage (Pidhorecky, 2000; DeMatteo, 2000). Both are associated with a worse prognosis.

On sonograms, larger GISTs appear as complex masses with cystic and solid components, which are consistent with their tendency to necrose (Shojaku, 1997; Tervahartiala, 1998).

Endoscopic ultrasonography can be valuable in the evaluation of GISTs. The tumors appear as hypoechoic masses that are contiguous with the fourth hypoechoic layer of the GI wall, which corresponds to the muscularis propria. Characteristics associated with malignancy include tumor size greater than 4 cm, an irregular extraluminal border, echogenic foci, and cystic spaces (Pidhorecky, 2000).

Degree of Confidence

Ultrasonography is only moderately sensitive for the detection and evaluation of the GIST. Bowel gas and acoustic shadowing obscures portions of the bowel and mesentery.

ANGIOGRAPHY

Section 8 of 11  

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• Ultrasound
• Angiography
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• Multimedia
• References

Findings

Angiography demonstrates a relatively well-circumscribed hypervascular lesion with central avascularity. They have large feeding arteries and draining veins, and they show intense tumor staining (Miettinen, 2000).

INTERVENTION

Section 9 of 11  

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• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Previously, the only proven treatment was surgical resection (DeMatteo, 2000; Lehnert, 1998). Radiation therapy and chemotherapy have been ineffective. However, the drug imatinib mesylate (STI-571; Novartis, Basel, Switzerland), sold under the trade name Gleevec in the United States, is currently being studied in clinical trials at several institutions.

Imatinib mesylate is an inhibitor of tyrosine kinases. These include the KIT receptor and the PDGRF receptors and their oncogenic activated forms (Tamborini, 2004).

As of late 2004, imatinib mesylate is in clinical stage 3 trials. The drug has proven effective in early- and late-stage disease. Posttreatment, liver lesions become better defined and cystlike (see Image 4).

Imatinib mesylate initially helps control disease in 80% or more of patients, with an objective response observed in 50-60% of cases; 10-15% had progression of disease despite therapy (Duffaud, 2003). Others develop resistance following initial responses. Factors thought to be involved include gene amplification and the presence of additional mutations, which may lend the GIST tumors an inherent resistance (Sawaki, 2004).

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

Media file 1:  Small-bowel gastrointestinal stromal tumor with a diffusely thickened bowel wall.
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Media file 2:  Gastrointestinal stromal tumor. Image obtained in the same patient as in Image 1. A more caudal portion of the tumor has areas of necrosis (arrows), with air present within the necrotic cavity that communicates with the lumen of the small bowel.
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Media type:  CT

Media file 3:  Small-bowel gastrointestinal stromal tumor with multiple liver metastases (arrows).
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Media file 4:  Gastrointestinal stromal tumor. Image obtained in the same patient as in Image 3 after imatinib mesylate (Gleevec) administration. Note the decreasing size of the liver metastases.
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Media type:  CT

Media file 5:  Multifocal gastrointestinal stromal tumors. Barium examination reveals a smooth mass that causes narrowing in the second portion of the duodenum (arrows).
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Media type:  X-RAY

Media file 6:  Gastrointestinal stromal tumor (GIST). CT scan obtained in the same patient as in Image 5 shows a focal segment of diffusely thickened ileum, which is another GIST.
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Media type:  CT

Media file 7:  Gastric gastrointestinal stromal tumor in a 49-year-old woman. The mass was found incidentally during an upper GI workup for peptic disease. The smooth appearance suggests a submucosal process.
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Media type:  X-RAY

Media file 8:  Gastrointestinal stromal tumor (GIST). Image obtained 1 year later in the patient in Image 7. The mass has increased in size. A GIST was found at surgery.
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Media file 9:  Gastrointestinal stromal tumor (GIST). CT scan obtained in the patient in Images 7-8 shows the same GIST. It appears as an intramural mass with both exophytic and endophytic components.
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Media type:  CT

Media file 10:  Gastric gastrointestinal stromal tumor (GIST) en face. Upper GI image obtained during the single contrast enhancement portion shows an incidentally found mass. The smooth borders suggest a submucosal process. At surgery, a GIST was found.
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Media type:  X-RAY

Media file 11:  Gastrointestinal stromal tumor with central bull's eye appearance, which is compatible with contrast material collection in an ulceration.
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Media type:  X-RAY

Media file 12:  Gastric gastrointestinal stromal tumor with huge exophytic component, which has become ulcerated. Barium collects in the exophytic ulcer crater (arrows).
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Media file 13:  Gastrointestinal stromal tumor (GIST). CT scan obtained in the patient in Image 12 demonstrates the GIST with large exophytic ulceration (arrows).
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Media file 14:  Proximal jejunal gastrointestinal stromal tumor that is completely exophytic and not visible at small-bowel barium examination.
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Media file 15:  Gastrointestinal stromal tumor (GIST). Contrast-enhanced CT obtained in the same patient as in Image 14 demonstrates a peripherally enhancing mass immediately adjacent to the pancreas that was thought to be a pancreatic neoplasm. However, at surgery, this was proved to be a proximal exophytic jejunal GIST.
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Media type:  CT

Media file 16:  Gastrointestinal stromal tumor. A 62-year-old women presented with 2 episodes of massive GI bleeding. Nuclear medicine GI bleed scanning demonstrates increased tracer activity in the mid abdomen (arrows) consistent with a small bowel active bleed. Courtesy of Dr Jon Wood and Dr John McDermott, University of Wisconsin Hospitals and Clinics.
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Media file 17:  Gastrointestinal stromal tumor (GIST). Patient in Image 16 then underwent angiography, which demonstrates a mass (white arrows) in the same location as the small-bowel bleed. The blood supply is from the superior mesenteric artery (red arrow). Minimal mass effect on the bladder is noted (yellow arrows). Findings are consistent with a small bowel mass, which stained positive for CD117; this result is consistent with a GIST.
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Media file 18:  Gastrointestinal stromal tumor. Selective masked injection in the superior mesenteric artery (red arrow) demonstrates a large arterial feeder with tumor staining (white arrows).
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Media file 19:  Gastrointestinal stromal tumor. Delayed images demonstrate large draining vein, which empties into the superior mesenteric vein (red arrow).
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Media file 20:  Gastrointestinal stromal tumor. Enteroclysis results were surprisingly normal. No abnormalities are seen, and no significant mass effect suggests the presence of the mass.
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Media file 21:  Gastrointestinal stromal tumor (GIST). CT demonstrates a complex mass originating from the small bowel with characteristics of a GIST.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT SCAN
• MRI
• Ultrasound
• Angiography
• Intervention
• Multimedia
• References

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• Seidal T, Edvardsson H. Diagnosis of gastrointestinal stromal tumor by fine-needle aspiration biopsy: a cytological and immunocytochemical study. Diagn Cytopathol. Dec 2000;23(6):397-401. [Medline].
• Shojaku H, Futatsuya R, Seto H, et al. Malignant gastrointestinal stromal tumor of the small intestine: radiologic-pathologic correlation. Radiat Med. May-Jun 1997;15(3):189-92. [Medline].
• Sircar K, Hewlett BR, Huizinga JD, et al. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol. Apr 1999;23(4):377-89. [Medline].
• Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology. Jul 2004;127(1):294-9. [Medline].
• Tazawa K, Tsukada K, Makuuchi H, Tsutsumi Y. An immunohistochemical and clinicopathological study of gastrointestinal stromal tumors. Pathol Int. Sep 1999;49(9):786-98. [Medline].
• Tervahartiala P, Halavaara J. Radiology of GIST. Gastrointestinal stromal tumours. Ann Chir Gynaecol. 1998;87(4):291-2. [Medline].

Article Last Updated: Dec 1, 2004