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Intestinal Stromal Tumors Workup

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

Laboratory Studies

Conduct a complete preoperative workup including blood panel, complete metabolic panel, and coagulation factors.

GISTs are not associated with elevation of any serum tumor markers. Performing tumor marker assays (eg, CA19-9, CEA, CA-125, AFP) for other abdominal neoplasms may be appropriate, however, depending on the location, size, and appearance of the tumor on imaging studies.

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Imaging Studies

The diagnostic 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.

  • A CT scan 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 contrast-enhanced CT scans, the intramural component of GIST is typically evident, though it may be more difficult to visualize large masses with extension into adjacent structures. Most of these tumors show peripheral enhancement with central areas of low attenuation suggesting hemorrhage, necrosis, or a cystic component. Typically, the enhancement is heterogeneous. 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.
  • MRI can be an especially helpful adjunct to CT in the evaluation of large tumors that have necrotic and hemorrhagic components. Solid tumor portions show low intensity on T1 images and high intensity on T2 images, with enhancement of the mass when intravenous gadolinium is given. Signal intensity of hemorrhagic components of the tumor can vary from high to low, depending on the age of the hemorrhage.

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. Focal areas of ulceration can be seen in 60% of cases.

Ultrasonography may suggest the presence of a malignant GIST, marked by cystic spaces, echogenic foci, and irregular extraluminal borders. Ultrasonography offers no benefit over CT or MRI, however, and so is rarely used if CT or MRI 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.[19]

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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. For small-bowel tumors, double-balloon endoscopy has proved effective for detection and biopsy of GISTs.[20]

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.

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Histologic Findings

On histology, as shown in images below, 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 neoplasm’s. 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.

Gastric stromal tumor. Photomicrograph of gastroin 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.
Photomicrograph of a gastric stromal tumor stained 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.

GISTs are distinguished from leiomyomas and leiomyosarcomas by immunohistochemistry and electron microscopy. Unlike the latter two tumor types, 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. The hallmark of GISTs is their positivity for CD117 (KIT) receptor, as shown in the image below. CD117 is the product of c-kit proto-oncogene.[21] 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. Although other tumors can be positive for CD117, most of these tumors do not occur in the GI tract. Additional mutually exclusive mutations from c-kit have also been identified in PDGFRA (10%) and BRAF (7%) genes, respectively, opening a role in tumorigenesis forothertyrosinekinases.[22]

Gastric stromal tumor: Photomicrograph of gastroin 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.

Assigning the risk of malignancy to GISTs tumors can be difficult. Many have observed the risk of recurrence varies by the anatomic location of the primary GIST. Miettinen et al proposed a risk assessment strategy.[23]

Table 2. Risk Classification for Primary GIST by Mitotic Index, Size, and Tumor Site. Adapted from AJCC. (Open Table in a new window)

Tumor Parameters Risk of Progressive Disease*
Mitotic



Index



Size Stomach Duodenum Jejunum



or ileum



Rectum
 



≤5 per 50 HPF



≤2cm None None None None
>2 to ≤5 cm Very low (1.9%) Low (8.3%) Low (4.3%) Low (8.5%)
>5 to ≤10 cm Low (3.6%) Insufficient data Moderate (24%) Insufficient data
>10 cm Moderate (10%) High (34%) High (52%) High (57%)
 



>5 per 50 HPF



≤2 cm None* Insufficient data High † High (54%)
>2 to ≤5 cm Moderate (16%) High (50%) High (73%) High (52%)
>5 to ≤10 cm High (55%) Insufficient data High (85%) Insufficient data
>10 cm High (86%) High (86%) High (90%) High (71%)
*Defined as metastasis or tumor-related death.



† Denotes small number of cases.



Data based on long-term follow up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.

 

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Staging

The American Joint Committee on Cancer (AJCC) has introduced new staging criteria for GISTs in its 7th edition manual.[24] There has never been AJCC staging for GISTs in the past, but this new scheme is to be used for all GISTs. The authors of this staging system adopted the accepted risk assessment for all GISTs and applied this to the tumor, node, metastasis (TNM) system.[23] In addition, a "grade" category is assigned based on mitotic rate: "low grade" for 5 or fewer mitoses in 50 HPF and "high grade" for 6 or more mitoses in 50 HPF. Staging is different for gastric and omental versus other GISTs, indicating a greater risk of recurrence for nongastric GISTs.

The new criteria for risk stratification of primary GISTs been incorporated into the AJCC staging seen below. The stratification is by mitotic index (5 or less or more than 5 per 50 HPF) and then further divided by tumor size, nodal disease, and tumor metastasis. Gastric GISTs larger than 10 cm but 5 or less per 50 HPF mitotic index have only a 10% risk of progressive disease despite 34-57% risk of progressive disease in the other tumor locations. Gastric GISTs greater than 10 cm and a high mitotic index (>5 per 50 HPF), however, have an equally high risk of progressive disease (86%) as the other tumor locations. Many studies have shown that tumor diameter greater than 5 cm is associated with increased risk for malignancy. However, the relationship of size to malignant potential may be gradual, with no clear cut-off point.

The number of mitotic figures is the most accepted index for grade classification, although other histologic parameters, such as cellularity, atypia, and necrosis, are also taken into consideration. A high mitotic index of more than 5 mitoses per 10 HPF usually signifies highly malignant disease. However, a low mitotic index is not always associated with a benign course. As many as 25% of tumors with mitotic index of less than 5 mitoses per 10 HPF may manifest aggressive biological behavior.

Tumor (T) is as follows:

  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • T1 - Tumor smaller than 2 cm, localized
  • T2 - Tumor more than 2 cm but not more than 5 cm
  • T3 - Tumor more than 5 cm but not more than 10 cm
  • T4 - Tumor rupture more than 10 cm in greatest dimension

Regional lymph node (N) is as follows:

  • N0 - No regional lymph node metastasis
  • N1 - Regional lymph node metastasis

Metastasis (M) is as follows:

  • M0 - No distant metastasis
  • M1 - Distant metastases

Table 3. Proposed Staging System for Malignant Gastrointestinal Stromal Tumors[24] (Open Table in a new window)

Group T N M Mitosis
Stage I T1 or T2 N0 M0 Low
Stage II T3 N0 M0 Low
Stage IIIA T1 N0 M0 High
  T4 N0 M0 Low
Stage IIIB T2 N0 M0 High
  T3 N0 M0 High
  T4 N0 M0 High
Stage IV Any T N1 M0 Any Rate
  Any T Any N M1 Any Rate
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Contributor Information and Disclosures
Author

Michael A Choti, MD, MBA, FACS Hall and Mary Lucile Shannon Professor and Chair, Department of Surgery, University of Texas Southwestern Medical Center

Michael A Choti, MD, MBA, FACS is a member of the following medical societies: American Association for the Study of Liver Diseases, American Surgical Association, International Hepato-Pancreato-Biliary Association, Americas Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American College of Surgeons, Association for Academic Surgery, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, Society of University Surgeons

Disclosure: Nothing to disclose.

Coauthor(s)

Fabian M Johnston, MD, MHS, FACS Assistant Professor, Department of Surgery, Johns Hopkins University School of Medicine

Fabian M Johnston, MD, MHS, FACS is a member of the following medical societies: American Medical Association, National Medical Association, Society of Black Academic Surgeons, Society of Surgical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

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, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Jules E Harris, MD, FACP, FRCPC Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Additional Contributors

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 Association for Physician Leadership, European Society for Medical Oncology, Association of Clinical Research Professionals, American Federation for Clinical Research, Eastern Cooperative Oncology Group, Society for Immunotherapy of Cancer, American Medical Informatics Association, American College of Physicians, American Federation for Medical Research, American Medical Association, American Society of Hematology, Massachusetts Medical Society

Disclosure: Nothing to disclose.

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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.
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.
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.
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.
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.
Liver resection specimen demonstrating 2 hepatic metastases from a gastrointestinal stromal tumor. Image courtesy of Michael Choti, MD.
Table 1. Survival in Patients Undergoing Resection of GISTs [12, 13, 14, 15, 16, 17]
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
Table 2. Risk Classification for Primary GIST by Mitotic Index, Size, and Tumor Site. Adapted from AJCC.
Tumor Parameters Risk of Progressive Disease*
Mitotic



Index



Size Stomach Duodenum Jejunum



or ileum



Rectum
 



≤5 per 50 HPF



≤2cm None None None None
>2 to ≤5 cm Very low (1.9%) Low (8.3%) Low (4.3%) Low (8.5%)
>5 to ≤10 cm Low (3.6%) Insufficient data Moderate (24%) Insufficient data
>10 cm Moderate (10%) High (34%) High (52%) High (57%)
 



>5 per 50 HPF



≤2 cm None* Insufficient data High † High (54%)
>2 to ≤5 cm Moderate (16%) High (50%) High (73%) High (52%)
>5 to ≤10 cm High (55%) Insufficient data High (85%) Insufficient data
>10 cm High (86%) High (86%) High (90%) High (71%)
*Defined as metastasis or tumor-related death.



† Denotes small number of cases.



Data based on long-term follow up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.
Table 3. Proposed Staging System for Malignant Gastrointestinal Stromal Tumors [24]
Group T N M Mitosis
Stage I T1 or T2 N0 M0 Low
Stage II T3 N0 M0 Low
Stage IIIA T1 N0 M0 High
  T4 N0 M0 Low
Stage IIIB T2 N0 M0 High
  T3 N0 M0 High
  T4 N0 M0 High
Stage IV Any T N1 M0 Any Rate
  Any T Any N M1 Any Rate
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