AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Until 20 years ago, gastrointestinal (GI) mesenchymal tumors were considered smooth muscle sarcomas (leiomyosarcomas). Unlike sarcomas, however, these GI sarcoma tumors were noted to be highly resistant to chemotherapy, compared with leiomyosarcoma. 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 (GIST). GISTs were defined by neoplasms showing incomplete or absent myogenic or neural pathology.

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.

GISTs rarely occur; they constitute only approximately 1% of all GI malignancies. GISTs can originate from any part of the GI tract, from the esophagus to the anus, but primarily occur in the stomach. They can 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

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

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. A relation between neurofibromatosis I and GISTs has also been postulated.

Mechanism of oncogenesis

The hallmark of GIST oncogenic potential is the constitutive activation of the KIT signaling pathway. 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. 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 KIT mutation is an early oncogenic event in GIST development. Familial predisposition to GIST formation has recently been associated with mutation in the PDGFR-α gene. Mutations of NF2 gene have also been reported in GISTs, but these mutations do not seem to be an integral part of GIST pathogenesis.

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. Sixty percent 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 following list, with part of the GI tract followed by frequency, summarizes the GIST distribution.²

• 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%

Mortality/Morbidity

In general, the 5-year survival rate after complete resection is estimated at 50-60% (see Table 1). Most recurrences are 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 GIST^{3, 4, 5, 6, 7}

The degree of mitosis on histology predicts mortality. For people 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 to 18-month median survival in people with higher mitotic rate.

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

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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 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 manifest 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, familiar disorders associated with underlying mutations of the KIT protein result in GIST oncogenesis (see Pathophysiology).

DIFFERENTIALS

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Other Problems to be Considered

Stomach
Adenocarcinoma
Lymphoma
Schwannoma
Desmoid fibromatosis
Smooth muscle neoplasm (leiomyoma, leiomyosarcoma)
Neuroendocrine neoplasms such as gastric carcinoid

Small bowel
Primary adenocarcinoma
Metastatic lesions to small bowel, especially melanoma
Lymphoma
Mesenteric tumors invading into small bowel (mesenteric fibromatosis, inflammatory pseudotumor, lymphoma, sclerosing mesenteritis, and metastatic disease)

Colon
Adenocarcinoma
Lymphoma
Metastatic melanoma
Leiomyosarcoma

Anorectum
Adenocarcinoma
Squamous cell carcinoma of the anus
Lymphoma
Malignant melanoma
Carcinoid

Esophagus
Adenocarcinoma
Squamous cell carcinoma
Leiomyoma, leiomyosarcoma
For intraluminal masses: carcinoma, papilloma, adenoma, and inflammatory or fibrovascular polyp
For small lesions in the esophageal wall: lipoma, granular cell tumor, duplication cyst

Mesentery and omentum
Sarcoma (liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, fibrosarcoma)
Mesenteric fibromatosis
Inflammatory pseudotumor

WORKUP

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Lab Studies

• Conduct a complete preoperative workup including blood panel, complete metabolic panel, and coagulation factors.
• Based on the location, size, and imaging studies of the GIST, other laboratory workup can include tumor markers for other abdominal neoplasms: CA19-9, CEA, CA-125, AFP. GISTs are not associated with an elevation of any serum tumor markers.

Imaging Studies

• Clinical pretherapeutic evaluation for GISTs is very similar to that pursued for other GI malignancies. Note that the appropriate imaging workup depends on the size and location of the tumor.
• Characteristic findings on computed tomography (CT) scan and magnetic resonance imaging (MRI) can be highly suggestive of a GIST versus other GI malignancies.
• • Computed tomography (CT) study of the abdomen and pelvis with oral and IV contrast is the most essential study to assess primary tumor extension and presence of metastasis, especially in the peritoneum or liver. On oral and intravenous CT scans, the intramural component of GIST is typically evident, though it may be more difficult for large masses with extension into adjacent structures. Most of the tumors show peripheral enhancement with central areas of low attenuation suggesting hemorrhage, necrosis, or a cystic component. Typically, the enhancement is heterogenous. Cavitary lesions may be present with air fluid levels. Metastatic lymphadenopathy is not a feature of GISTs. Metastatic disease may be evident with CT findings consistent with organ invasion, ascites, omental or peritoneal spread, or liver metastasis.
  • Magnetic resonance imaging (MRI) can also be very helpful. MRI findings can be variable. Based on the degree of necrosis and hemorrhage, the signal intensity pattern can vary. Solid tumor portions show low intensity on T1 images and high intensity on T2 images with enhancement of the mass upon intravenous gadolinium. Hemorrhagic components of the tumor can vary from high to low signal intensity based on the age of the hemorrhage. MRI can be an especially helpful adjunct to CT in the evaluation of large tumors with hemorrhagic and necrotic components to them. Barium and Gastrografin studies of the stomach, small intestine, and colon aid in the diagnosis of GISTs. These studies include upper gastrointestinal series, small bowel series, and barium enema studies. Typically, the lesions have the classic features of submucosal masses such as leiomyomas and leiomyosarcomas. They appear as a smooth-lined filling defect in the lumen with well-demarcated borders. Sixty percent of the time, focal areas of ulceration may be present
• Ultrasonography may suggest the presence of a malignant GIST, marked by cystic spaces, echogenic foci, and irregular extraluminal borders. Ultrasonography has no benefit compared to CT or MRI; therefore, the former modality is rarely used if the latter two provide sufficient information for a tentative diagnosis.
• Fluorodeoxyglucose positron emission tomography (FDG-PET) scanning may be helpful in the staging and evaluation of GISTs. Its value has been reported in studying disease progression or response to therapy in people receiving imatinib for primary or metastatic GISTs.

Procedures

Procedures performed in the evaluation of GISTs are similar to those used for other GI malignancies. Base the choice of procedure on the location and size of the mass and the need for any further information after pursuing imaging modalities.

For tumors of the upper GI tract, esophagogastroduodenoscopy may aid in the extent of intraluminal involvement and in obtaining definitive tissue diagnosis. Typically, they appear as a submucosal mass. Any endoscopic biopsy, however, needs to be deep enough to obtain tissue below the mucosa.

GISTs typically appear as a smooth protrusion of the bowel wall with preserved mucosal lining and may have components of ulceration and bleeding. Endoscopic ultrasonography may show a hypoechoic mass originating in the muscularis propria of the bowel wall. Similarly, anorectal ultrasonography and colonoscopy can provide findings consistent with GISTs of the colon, rectum, and anus.

Histologic Findings

On histology, spindle-shaped cells are most common (70%), followed by epithelioid cells (20%) and a mixed spindle cell-epithelioid pattern. The tumor cells are highly cellular with less eosinophilic cytoplasm than smooth muscle neoplasms. They have indistinct cell margins and minimal tumor stroma. Malignancy is associated with histology consistent with nuclear atypia, high cellularity, high mitotic rate (more than 5 per HPF), mucosal invasion, necrosis, and a mixed spindle cell-epithelioid morphology (see Images 3-4).

GISTs are distinguished from leiomyomas and leiomyosarcomas by immunohistochemistry and electron microscopy. Unlike the latter two, GISTs are usually positive for CD34 (60-70%). They may be positive for smooth muscle actin, but unlike smooth muscle tumors, GISTs are rarely positive for desmin. Unlike smooth muscle neoplasms, GISTs may not have thin actin filaments with periodic densities on electron microscopy. The hallmark of GISTs is their positivity for CD117 (KIT) receptor, the product of c-kit proto-oncogene. Gain of functional mutations of the KIT protein, a tyrosine kinase receptor, is believed to play a critical role in the oncogenesis of GISTs. Although other tumors can be positive for CD117, most of these tumors do not occur in the GI tract (see Image 5).

The above information helps distinguish GISTs from other GI neoplasms, but assigning the risk of malignancy to these tumors can still be difficult. Many tumors are graded as having low malignant potential due to this difficulty. Fletcher et al (2002) proposed a risk assessment strategy (Table 2).⁸

Table 2. Risk Stratification of GIST Based on Histology

Staging

No absolute consensus has been reached on a staging system for GISTs. Although there is a staging system for sarcomas, it is not helpful in accurately staging GISTs. A risk assessment for malignant potential of GISTs is available that is based on the tumor size and mitotic index on histology. Overall, assessing the malignant potential of GISTs remains difficult.

Even small GISTs are often read as having low malignant to uncertain malignant potential. The tumor location changes the criteria used to predict biological behavior, which further complicates determining the malignant potential. Tumors originating from the small bowel, mesentery, colon, and rectum are often associated with a less favorable outcome than those associated with the stomach. The two most important prognostic predictors of behavior are tumor size and mitotic index on histology. Of course, overt metastasis is a clear indication of malignancy.

Tumors of the esophagus and colon are generally malignant, whereas gastric GISTs are more frequently indolent tumors. GISTs larger than 5 cm are generally malignant, whereas almost all incidentally detected GISTs (<1 cm) are typically benign. No exact cut-off diameter that accurately predicts malignancy, in addition, diameter can be variable based on tumor location.

The mitotic rate is another important factor that helps predict biological behavior of GISTs. As shown in Table 2, mitotic rate and tumor size could be used to provide a general idea of the malignant potential of a GIST.

TREATMENT

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Medical Care

In general, attempts to treat GISTs with cytotoxic chemotherapy or radiation therapy have been unsuccessful. Effects of radiation therapy on survival are unknown. GISTs are not ideal for this modality because of intra-abdominal motility, and for large tumors, the required field of radiation exposure may cause too much morbidity. Postoperative radiation therapy has managed fixed GISTs, but the results have not been exciting. Recurrences are reported both within and outside the radiation field. Most often, radiation therapy is used in the palliative setting for symptomatic, unresectable disease.

Standard cytotoxic chemotherapy has not been helpful in GIST management. One report noted only a 7% response rate (3 of 43 people with GISTs) to doxorubicin and dacarbazine in gastric sarcomas, compared to 22% for leiomyosarcomas. Other chemotherapy combinations have been equally unsuccessful.

Imatinib mesylate (Gleevec), a tyrosine kinase inhibitor, is the first drug that effectively showed response rates against GIST progression. Two important studies support a major role for Imatinib in the treatment of GISTs.

• Demetri et al (2001) reported a 54% response rate in 147 people with metastatic GISTs upon treatment with 400-600 mg of daily imatinib and at least 6 months of follow-up. A minor response was recorded in 28%, and 14% had resistance to the drug.⁹
• van Oosterom et al (2001), in a phase I trial, reported a 53% response rate in 36 people with metastatic GISTs on a minimum 9-month follow-up. Only 11% showed absolute resistance, 11% had stable tumor loads, and 17% showed minor response.¹⁰
• Both these mentioned studies reported approximately 90% improvement in clinical symptoms.

Surgical Care

Surgical resection remains the cornerstone of treatment for localized GISTs. A complete resection offers the only chance for cure. Patients with complete tumor resection have a clear survival benefit over those with less radical or no surgery. Complete resection is associated with approximately 50-65% 5-year survival rate, but more than 50% of patients who undergo primary resection develop tumor recurrence (see Table 1 in Mortality/Morbidity).

For small GISTs, local resection may be adequate, if technically possible and it does not compromise a complete resection. Small intestinal tumors may require segmental resection, and a wedge resection may be used for small gastric GISTs in some cases. Avoid enucleation of small tumors since predicting the preoperative malignant potential of GISTs is difficult, even if the tumor appears benign. Since limited resection is adequate for small malignant GISTs, minimally invasive surgery techniques can be adopted in select cases. Laparoscopic resection of GISTs of the stomach has demonstrated the feasibility and safety of this technique.

Approach all GISTs with an intention of a complete en bloc resection, including resection of any involved organs or structures such as the colon, spleen, kidney, and pancreas. As GISTs rarely metastasize to lymph nodes, routine lymphadenectomy is not indicated and does not show any survival benefit. Direct all efforts at avoiding tumor rupture during the operation. A tumor rupture is associated with a worse prognosis due to peritoneal seeding. Similarly, preoperative percutaneous biopsy of the tumor is not indicated in most cases, because there is a potential for needle track seeding. Preoperative percutaneous biopsy is pursued if the newly available information changes management, as it would in the case of a lymphoma.

The role for surgery in treating GIST metastasis is minimal. Metastasectomy may provide a survival benefit in select patients. These may include patients with well-differentiated GISTs, longstanding disease-free survival, and isolated liver metastases. In patients with good response to imatinib treatment, in whom gross disease can be removed, surgery may be considered on an individual case-by-case basis.

Consultations

No specific consultations are required.

Diet

Diet advancement decisions in people who have had surgery are based on the type of surgery and are individualized for each person. No specific diet restrictions are recommended for people with GISTs.

Activity

No specific activity restrictions exist.

MEDICATION

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The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Tyrosine kinase inhibitors

These agents inhibit the activation of tyrosine kinases, which halt their downstream signal cascades.

Drug Category: Multikinase inhibitors

These agents elicit actions via multiple tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

FOLLOW-UP

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Further Inpatient Care

No specific changes in routine postoperative or other inpatient care requirements exist. Inpatient care for postoperative patients is similar to that for other GI surgery patients. Care is individualized to each patient.

Further Outpatient Care

• Follow-up care after curative operations is important because certain patients with recurrent disease may benefit from second surgical intervention and from systemic therapy with imatinib mesylate or chemotherapy for unresectable and metastatic disease. Follow-up includes physical examination and periodical gastroscopies and CT scans. Time intervals for performing these studies are not defined.
• These tumors metastasize to the lungs in only about 2% of cases. Therefore, if findings are negative on an initial staging CT scan of the chest, additional evaluation for lung metastases may be obtained with chest X-rays alone.

Complications

• In patients with operative intervention for their GISTs, postoperative complications depend on the nature of surgery, patient comorbidities, the extent of resection, and the malignant potential of the tumor. In the immediate postoperative period, the list of complications is no different from those for other GI surgeries.
• Patients undergoing medical intervention are at risk for complications based on the intervention they receive. Chemotherapeutic interventions lead to similar risk profile for complications as seen with such intervention for other tumors.

Prognosis

• In general, tumor size and histological grade strongly relate to long-term survival for malignant GIST after a curative-intent surgery. The 3 primary predictors of improved prognosis are (1) complete resectability of the tumor, (2) tumor size, and (3) tumor grade.
• Comparison of the different published survival rates is difficult because no standardized staging system exists for stromal tumors of the GI tract and most series are small and heterogenous. However, various reports of 5-year survival rates after complete resection, with negative margins (R0) for gastric sarcoma range from 32-93%. In large series, this rate is about 60% (see Table 1 in Mortality/Morbidity). The median survival after palliative resection is about 10 months, with a 5-year survival rate as high as 10%.
• Histopathology and clinical features of GISTs affect prognosis. Median survival is 5 years for primary disease, but only 10-20 months for metastatic or recurrent disease. The grade on histology also strongly correlates with prognosis. In one study, patients with GISTs less than 5 mitoses per 50 cells on HPF had a median survival of 98 months, while those with GISTs greater than 10 mitoses had a median survival of 25 months. Other factors that have a negative impact on prognosis are tumor rupture during operation, involvement of margins, and lymph node involvement.
• The liver and peritoneal cavity represent the predominant sites of recurrence after attempted curative surgery. Compared to other soft tissue sarcomas, metastasis to extra-abdominal sites (eg, lungs) is infrequent. Evaluate patients with recurrent disease for potential second resection. Survival prolongation is reported for resected local recurrences and even for resected isolated hepatic or peritoneal recurrent lesions (see Image 6).

Patient Education

For excellent patient education, visit eMedicine's Cancer Screening Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer of the Small Intestine, Stomach Cancer, and Cancer: What You Need to Know.

MISCELLANEOUS

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Medical/Legal Pitfalls

• No consensus has been reached regarding a uniform staging system, and none of the currently used classifications is fully satisfactory.
• No standard regimen for adjuvant therapy presently exists for malignant gastric stromal tumors.
• Direct every effort at avoiding tumor rupture during surgical therapy. Tumor rupture is associated with a worse prognosis due to peritoneal seeding.
• Because malignant potential is difficult to determine preoperatively, a wide resection with clear margins is routinely indicated.

MULTIMEDIA

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Media file 1:  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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Media file 2:  CT scan of the abdomen with oral contrast in a 60-year-old woman with gastric stromal tumor. A huge mass with central necrosis is observed originating from the gastric wall and narrowing its lumen. An ulcer crater can be identified within the mass (arrow). Image courtesy of Michael Choti, MD.
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Media type:  CT

Media file 3:  Gastric stromal tumor. Photomicrograph of gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 40 times. Note the solid sheet of spindle cells. Image courtesy of Michael Choti, MD.
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Media type:  Photo

Media file 4:  Photomicrograph of a gastric stromal tumor stained with hematoxylin and eosin (H&E) and magnified 400 times. This stromal tumor demonstrates spindle cells with epithelioid features. Image courtesy of Michael Choti, MD.
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Media type:  Photo

Media file 5:  Gastric stromal tumor: Photomicrograph of gastrointestinal stromal tumor (GIST) with immunohistochemical staining for CD117. Note the strong positive staining of tumor cells with negative staining of the adjacent vessel. Positive stain for CD117 is diagnostic of GIST. Image courtesy of Michael Choti, MD.
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Media type:  Photo

Media file 6:  Liver resection specimen demonstrating 2 hepatic metastases from a gastrointestinal stromal tumor. Image courtesy of Michael Choti, MD.
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Media type:  Photo

REFERENCES

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19. Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. Jan 2004;126(1):318-21. [Medline].
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Article Last Updated: Sep 11, 2007