Gastrointestinal Stromal Tumors (GISTs) 

Updated: Sep 28, 2016
Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS 

Overview

Practice Essentials

Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, but they are the most common mesenchymal neoplasms of the GI tract. GISTs are usually found in the stomach or small intestine but can occur anywhere along the GI tract and rarely have extra-GI involvement. See the image below.

Shown here is a gastric gastrointestinal stromal t Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.

Signs and symptoms

Up to 75% of GISTs are discovered when they are less than 4 cm in diameter and are either asymptomatic or associated with nonspecific symptoms. They are frequently diagnosed incidentally during radiologic studies or endoscopic or surgical procedures performed to investigate the GI tract disease or to treat an emergent condition such as hemorrhage, obstruction, or perforated viscus. Clinical manifestations of GISTs are as follows:

  • Vague, nonspecific abdominal pain or discomfort (most common)
  • Early satiety or a sensation of abdominal fullness
  • Palpable abdominal mass (rare)
  • Malaise, fatigue, or exertional dyspnea with significant blood loss
  • Focal or widespread signs of peritonitis (with perforation)

Obstructive signs and symptoms of GISTs can be site-specific, as follows:

  • Dysphagia with an esophageal GIST
  • Constipation and a distended, tender abdomen with a colorectal GIST
  • Obstructive jaundice with a duodenal GIST

See Presentation for more detail.

Diagnosis

No laboratory test can specifically confirm or rule out the presence of a GIST. The following tests are generally ordered in the workup of patients who present with nonspecific abdominal symptoms; abdominal pain; or complications such as hemorrhage, obstruction, or perforation:

  • Complete blood cell count
  • Coagulation profile
  • Serum chemistry studies
  • BUN and creatinine
  • Liver function tests, amylase and lipase values
  • Type, screen, and crossmatch
  • Serum albumin

Imaging studies

Plain abdominal radiography:

  • Nonspecific
  • May be part of an emergent workup
  • Abnormal gas patterns, including dilated loops of bowel or free extraluminal air, may be seen with bowel obstruction or perforation

Barium and air (double-contrast) series:

  • Frequently provides only limited information
  • Can usually detect GISTs that have grown to a size sufficient to produce symptoms
  • Barium swallow for patients with dysphagia
  • Barium enema for patients with constipation, decreased stool caliber, or colonic manifestations
  • GISTs appear as an elevated, sharply demarcated filling defect
  • The overlying mucosa typically has a smooth contour unless ulceration has developed

Computed tomography scans of the abdomen and pelvis:

  • Essential for the diagnosis and staging of GISTs
  • Provides comprehensive information regarding the size and location of the tumor and its relationship to adjacent structures
  • Can also be used to detect the presence of multiple tumors and of metastatic spread

CT characteristics of small GISTs (< 5 cm) are as follows[1] :

  • Sharply demarcated
  • Homogeneous density
  • Mainly exhibit intraluminal growth patterns

CT characteristics of intermediate GISTs (5-10 cm) are as follows[1] :

  • Irregular shape
  • Heterogeneous density
  • An intraluminal and extraluminal growth pattern
  • Signs of biological aggression, sometimes including adjacent organ infiltration [1]

CT characteristics of large GISTs (>10 cm) are as follows[1] :

  • Irregular margins
  • Heterogeneous densities
  • Locally aggressive behavior
  • Distant and peritoneal metastases

CT criteria associated with high-grade histology and increased mortality:

  • Tumor larger than 11.1 cm
  • Irregular surface contours
  • Indistinct margins
  • Adjacent organ invasion
  • Heterogeneous enhancement
  • Hepatic or peritoneal metastasis

Magnetic resonance imaging:

  • Like CT scanning, MRI can depict tumors and yield information about surrounding structures
  • Can also be used to detect the presence of multiple tumors and metastases
  • Less well studied than CT for diagnosing GISTs, but appears equally sensitive [2]
  • GISTs may appear hypointense on T2-weighted images

Positron emission tomography scanning with 2-[F-18]-fluoro-2-deoxy-D-glucose has the following uses:

  • Detection of metastatic disease
  • Monitoring of response to adjuvant therapy (eg, imatinib mesylate)

Endoscopy:

  • Frequently performed early in the workup of patients with GI bleeding, abdominal pain, or GI obstructive symptoms from GISTs
  • Endoscopic features of GISTs include the suggestion of a smooth submucosal mass displacing the overlying mucosa
  • Ulceration or bleeding of the overlying mucosa from pressure necrosis may be present
  • Problematic for biopsy specimen collection because of the submucosal location of GISTs
  • Endoscopic biopsy results yield a diagnosis in less than 50% of cases
  • Obtaining a repeat biopsy in the same site as a prior biopsy may increase the diagnostic yield

Endoscopic ultrasonography (EUS):

  • Allows localization of lesions and their characterization by ultrasonography
  • Fine-needle aspiration biopsy specimens may be obtained under sonographic guidance
  • GISTs typically appear as a hypoechoic mass in the layer corresponding to the muscularis propria
  • Complementary with CT
  • More accurate than CT in differentiating benign from malignant lesions
  • Allows a more comprehensive evaluation of the mass and the surrounding structures than CT

EUS characteristics of malignant GISTs include the following:

  • Size larger than 4 cm (the only independent predictor)
  • Heterogeneous echogenicity
  • Internal cystic areas
  • Irregular borders on the extraluminal surfaces

EUS features that may help differentiate gastric GISTs from leiomyomas are as follows[3] :

  • Inhomogenicity
  • Hyperechogenic spots
  • A marginal halo
  • Higher echogenicity than the surrounding muscle layer

Aspects of EUS-guided biopsy are as follows:

  • Biopsy provides definitive diagnosis
  • Biopsy may be required when preoperative therapy is needed in cases where the tumor is unresectable or only marginally resectable
  • Biopsy may not be necessary if the tumor is surgically resectable and preoperative medical therapy is not required

See Workup for more detail.

Management

Surgery is the definitive therapy for patients with GISTs, as follows:

  • Radical and complete surgical extirpation offers the only chance for cure
  • Surgery is also indicated in symptomatic patients with locally advanced or metastatic disease
  • Debulking large lesions is helpful when adjuvant therapy is contemplated
  • Laparoscopic resection has improved and is a more frequently considered option

Imatinib mesylate is used in GIST as follows:

  • Adjuvant therapy post complete surgical resection in patients with high-risk tumors
  • Neoadjuvant therapy with the goal of tumor shrinkage prior to surgical resection

Other tyrosine kinase inhibitors are used when imatinib is not tolerated or is not effective are as follows:

  • Sunitinib: Less specific than imatinib; approved as a second-line agent for advanced GIST
  • Sorafenib: Investigational second-generation agent
  • Dasatinib: Investigational second-generation agent
  • Nilotinib: Investigational second-generation agent

See Treatment and Medication for more detail.

Background

Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors, with only about 5000 new cases expected annually in the United States. GISTs rank a distant third in prevalence behind adenocarcinomas and lymphomas among the histologic types of GI tract tumors. However, GISTs are the most common mesenchymal neoplasms of the GI tract. See the image below.

Shown here is a gastric gastrointestinal stromal t Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.

GISTs are usually found in the stomach or small intestine but can occur anywhere along the GI tract. Rarely, GISTs have extra-GI involvement.[4]

Historically, these lesions were classified as leiomyomas or leiomyosarcomas because they possessed smooth muscle features when examined under light microscopy. In the 1970s, electron microscopy found little evidence of smooth muscle origin of these tumors. In the 1980s, with the advent of immunohistochemistry, it was shown that these tumors did not have immunophenotypic features of smooth muscle cells and rather expressed antigens related to neural crest cells. Mazur and Clark in 1983, and Schaldenbrand and Appleman in 1984, were the first to describe "stromal tumors" as a separate entity.

According to the work of Kindblom and associates, reported in 1998, the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal.[5] These are GI pacemaker cells found in the muscularis propria and around the myenteric plexus and are largely responsible for initiating and coordinating GI motility. This finding led Kindblom and coworkers to suggest the term GI pacemaker cell tumors.[5]

Additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor, which is regulated through KIT kinase. Perhaps the most critical development that distinguished GISTs as a unique clinical entity was the discovery of c-KIT proto-oncogene mutations in these tumors in by Hirota and colleagues in 1998.[6]

Activating KIT mutations are seen in 85-95% of GISTs. About 3-5% of the remainder of KIT-negative GISTs contain PDGFR-alpha mutations.[7, 8, 9]

 The PDGFR alpha mutation seems to leave the PDGFRalpha receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor. The discovery of these receptor mutations has redefined the classification and management of the disease.

The discovery in 2000 that the tyrosine kinase inhibitor (TKI) imatinib, initially used to treat chronic myeloid leukemia, is effective in treating metastatic GISTs revolutionized the care of patients with GISTs.[10] Imatinib has been shown to target KIT and PDGFR alpha in KIT receptor-positive GIST.[11, 12, 13, 14, 15]

This discovery has been celebrated as the example of the power of targeted, individualized therapy and has helped focus a great deal of attention on this orphan disease. The US Food and Drug Administration (FDA) approved imatinib for treatment of metastatic GIST in 2002 and for the adjuvant therapy of primary resected GIST in 2008.[4] The FDA has also approved the newer tyrosine kinase inhibitors sunitinib and regorafenib for treatment of GISTs that are unresponsive to imatinib.

Pathophysiology

GISTs are typically diagnosed as solitary lesions, although in rare cases (ie, pediatric type), multiple lesions can be found. These tumors have been reported to range in size from smaller than 1 cm to as large as 40 cm in diameter.[16] GISTs can grow intraluminally or extraluminally toward adjacent structures. When the growth pattern is extraluminal, patients can harbor the disease symptom free for an extended period and present with very large exogastric masses.

Approximately 50-70% of GISTs originate in the stomach. Of those, 15% occur in the cardia and fundus, 70% in the body, and 15% in the antrum).[17] The small intestine is the second most common location, with 20-30% of GISTs arising from the jejunoileum. Less frequent sites of occurrence include the colon and rectum (5-15%) and esophagus (< 5%). Primary pancreatic, omental, or mesenteric GISTs have been reported but are very rare.[18]

Distant metastases tend to appear late in the course of the disease in most cases. In contrast to other soft tissue tumors, the common metastatic sites of GISTs are the liver and peritoneum. Lymph node involvement is rare, occurring in only 0-8% of cases. However, in rare cases of pediatric GIST, lymph nodes are commonly involved, and distant metastasis is present at diagnosis.[19] Despite these metastases, these variant GISTs have an indolent clinical course.

Epidemiology

Frequency

Roughly 5000 new cases of GISTs are diagnosed annually in the United States. According to the Surveillance, Epidemiology, and End Results (SEER) database, the annual age-adjusted incidence of GISTs rose from 0.55 per 100,000 population in 2001 to 0.78/100,000 in 2011.[20]

Data on worldwide frequency are limited, but in general, GISTs constitute 1-3% of all gastric malignancies. Population-based studies from Iceland, the Netherlands, Spain, and Sweden report annual incidence rates ranging from 6.5 to 14.5 cases per million.[21, 22, 23, 24]

Mortality/Morbidity

According to 2001-2011 SEER data, 5-year overall survival rates for patients with GISTs are 77% for those with localized disease at diagnosis, 64% for those with regional disease, and 41% for those with metastatic disease.[20]

Gastric GISTs carry a better prognosis than small bowel GISTs of similar size and mitotic rate. In general, gastric GISTs portend a much better prognosis than adenocarcinoma of the stomach.

Even after complete resection of primary GIST, at least 50% of patients develop recurrence or metastasis, at a median time to recurrence of 2 years. This high rate of recurrence is in the setting of an overall 5-year survival rate of 50%.

Larger GISTs are associated with complications such as GI hemorrhage, GI obstruction, and bowel perforation. Patients with advanced GISTs who are receiving tyrosine kinase inhibitor therapy may develop tumor-related intraluminal or intraperitoneal hemorrhage, rupture, fistula, or obstruction requiring emergent surgery.

Race-, Sex-, and Age-related Demographics

A review of the SEER database from 2001-2011 found that GISTs were more common in non-Hispanics than Hispanics (rate ratio [RR]=1.23) and in blacks (RR=2.07) or Asians/Pacific Islanders (RR=1.50) than in whites. GISTs were also more common in males than females (RR=1.35). The incidence of GISTs increased with age, peaking among 70-79 year olds.[20]

Older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors of worse overall survival, on multivariate analysis. Those characteristics, along with earlier year of diagnosis, were also independent risk factors of worse GIST-specific survival.[20]

 

Presentation

History

Many gastrointestinal stromal tumors (GISTs) are discovered incidentally during endoscopic or surgical procedures. In Japan, mass screening for gastric adenocarcinoma with upper endoscopy has led to an increase in incidental findings of asymptomatic GISTs.

Other GISTs are detected on radiologic studies performed to investigate protean manifestations of GI tract disease or procedures performed to treat an emergent condition such as hemorrhage or obstruction. In a population-based study, the median tumor size of GISTs that were detected as incidental findings was 2.7 cm, versus 8.9 cm for those found on the basis of symptoms.[24]

GISTs may produce symptoms secondary to hemorrhage or obstruction. Upper GI bleeding is the most common clinical manifestation of GISTs, manifesting as hematemesis or melena in 40-65% of patients. Bleeding occurs because of pressure necrosis and ulceration of the overlying mucosa with resultant hemorrhage from disrupted vessels. Patients who have experienced significant blood loss may report malaise, fatigue, or exertional dyspnea.

Obstruction can result from intraluminal growth of an endophytic tumor or from luminal compression from an exophytic lesion. The obstructive symptoms can be site-specific (eg, dysphagia with an esophageal GIST, constipation with a colorectal GIST, obstructive jaundice with a duodenal tumor). Other symptoms are generally associated with an enlarging abdominal mass and may include the following:

  • Abdominal pain
  • Anorexia
  • Nausea
  • Vomiting
  • Weight loss
  • Epigastric fullness
  • Early satiety

Physical Examination

Physical examination rarely demonstrates any significant findings. In some cases, examination may identify a palpable mass in the abdomen. Palpable masses are typically detected in patients with extraluminal tumor growth.

Other patients may present with nonspecific physical findings associated with GI blood loss, bowel obstruction, or bowel perforation and abscess formation.

Patients with significant GI bleeding may present with abnormal vital signs or overt shock. In others, fecal occult blood testing may be positive.

Physical findings associated with bowel obstruction can include a distended, tender abdomen. Duodenal obstruction involving the ampulla may be associated with jaundice and, rarely, even a distended palpable gallbladder.

If perforation has occurred, focal or widespread signs of peritonitis are present.

Causes

Most GISTs are associated with gain-of-function mutations in exon 11 of the c-kit proto-oncogene., which encodes the transmembrane tyrosine kinase KIT.[25] The c-kit proto-oncogene is located on chromosome arm 4q11-12. Most of these mutations are of the in-frame type, which allows preservation of c-kit expression and activation.

Stem cell factor, also called Steel factor or mast cell growth factor, is the ligand for KIT. Under normal circumstances, KIT activation is initiated when stem cell factor binds to the extracellular domain of c-Kit. The result is homodimerization of the normally inactive c-Kit monomers. Autophosphorylation of intracellular tyrosine residues then occurs, exposing binding sites for intracellular signal transduction molecules.

What follows is activation of a signaling cascade that involves phosphorylation of several downstream target proteins, including MAP kinase, RAS, and others. Ultimately, the signal is transduced into the nucleus, resulting in mitogenic activity and protein transcription.

In the majority of GISTs, KIT is constitutively phosphorylated and does not require stem cell factor for initiation of the sequence of c-Kit homodimerization and autophosphorylation. This is termed ligand-independent activation. The increased transduction of proliferative signals to the nucleus favors cell survival and replication over dormancy and apoptosis, leading to tumorigenesis.[26]

Although 95% of GISTs are KIT positive, 5% of GISTs have no detectable KIT expression. In a proportion of these KIT-negative GISTs, mutations occur in the PDGFRA gene rather than KIT. Immunostaining with PDGFRA has been shown to be helpful in discriminating between KIT-negative GISTs and other gastrointestinal mesenchymal lesions.

BRAF mutations and protein kinase C theta (PKCtheta) have also been reported in a small proportion of GISTs lacking KIT/PDGFRA. 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.[27] 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.[28]

A small minority of GISTs are associated with hereditary syndromes. Familial GISTs are characterized by inherited germline mutations in KIT or PDGFRA and additional findings such as the following:

  • Cutaneous hyperpigmentation
  • Irritable bowel syndrome
  • Dysphagia
  • Diverticular disease

Of individuals with these germline mutations, 90% may develop GISTs by 70 years of age. Patients with germline autosomal dominant mutations of KIT may present with multiple GISTs at an early age.[29] However, familial GISTs have favorable outcomes and do not appear to be associated with shortened survival. No data support preventive therapy in patients with these germline mutations.

In addition, the following syndromes are linked to GISTs[29] :

  • Carney triad - gastric GISTs, paraganglioma, and pulmonary chondromas (these may occur at different ages); primarily affects young women [30]
  • Carney-Stratakis syndrome - GIST and paraganglioma
  • Neurofibromatosis type 1 - Wild-type, often multicentric GIST, predominantly located in the small bowel
 

DDx

Diagnostic Considerations

When evaluating patients with suspected GISTs, include the following conditions in the differential diagnosis:

  • Epithelioid hemangioendothelioma
  • Fibromatosis
  • Lymphoma
  • Metastatic melanoma
  • Schwannoma
  • Leiomyoma

The differential diagnosis for gastric stromal tumors includes benign lesions such as true leiomyoma, schwannoma, lipoma, ectopic pancreas, and sarcomas.[31] Other possible lesions include the much more common gastric adenocarcinoma and other rare submucosal malignant tumors such as lymphoma and carcinoid.

Not infrequently, patients with GISTs of the stomach present with a large mass in the epigastrium or left upper quadrant. In such cases, the differential diagnosis may include masses originating from other organs such as the liver, spleen, pancreas, left adrenal gland, or retroperitoneum.

Differential Diagnoses

 

Workup

Laboratory Studies

No laboratory test can specifically confirm or rule out the presence of a gastrointestinal stromal tumor (GIST). The following tests are generally ordered in the workup of patients who present with nonspecific abdominal symptoms; abdominal pain; or findings that may be due to complications of GISTs, such as hemorrhage, obstruction, or perforation:

  • Complete blood cell count
  • Coagulation profile
  • Serum chemistry studies
  • BUN and creatinine
  • Liver function tests
  • Amylase and lipase values
  • Blood type, screen, and crossmatch
  • Serum albumin

GISTs are not associated with elevation of any serum tumor markers. However, depending on the location, size, and appearance of the tumor on imaging studies, performing tumor marker assays such as the following for other abdominal neoplasms may be appropriate:

  • Cancer antigen 19-9 (CA19-9)
  • Carcinoembryonic antigen (CEA)
  • CA-125
  • Alpha fetoprotein (AFP)

Imaging Studies

Imaging studies used in the workup of GISTs include the following:

  • Radiography
  • Ultrasonography
  • Computed tomography (CT)
  • Magnetic resonance imaging (MRI)
  • Positron emission tomography (PET)

Radiography

Plain abdominal radiography is nonspecific but may be ordered as part of the workup of a patient presenting emergently with a possible bowel obstruction or perforation. Abnormal gas patterns, including dilated loops of bowel or free extraluminal air, are examples of findings that may be detected in these clinical situations.[32]

Barium and air (double-contrast) series

Double-contrast radiographic series can usually detect GISTs that have grown to a size sufficient to produce symptoms. The choice of performing a barium swallow, barium enema, or both depends on the patient's clinical presentation. For example, patients whose primary symptomatology includes dysphagia should have a barium swallow. Those presenting with constipation, decreased stool caliber, or other signs and symptoms referable to the colon should have a barium enema.

In these contrast studies, GISTs appear as a filling defect that is sharply demarcated and is elevated compared with the surrounding mucosa.[33] Typically, the contour of the overlying mucosa is smooth unless ulceration has developed because of growth of the underlying tumor.

While these studies can produce striking images, frequently the information they provide is limited. Other modalities listed below have equal or greater sensitivity and can provide more information about the status of the surrounding structures.

Enteroclysis

As is frequently the case with other small bowel lesions, GISTs in the small intestine can be difficult to diagnose and localize. Enteroclysis allows delivery of contrast into the small bowel so it does not become too diluted by the time it reaches the area in question. This may help to better define small intestinal GISTs.

Ultrasonography

The ultrasonographic appearance of GISTs varies depending on the size of the lesion and the presence or absence of necrosis within the mass. In addition, ulceration or necrosis of the overlying mucosa can change the ultrasonographic characteristics of the tumor.

Transcutaneous ultrasonography is probably not the optimum choice for imaging these lesions unless the mass has reached quite a large size. Because GISTs are associated with air-filled viscera, image quality is often degraded by intervening bowel gas.

The best ultrasonographic images of these lesions are acquired during endoscopic ultrasonography (see Procedures).

Computed tomography

CT scanning with intravenous and oral contrast material is a necessary step in the diagnosis and staging of GISTs.[29] It provides comprehensive information regarding the size and location of the tumor and its relationship to the adjacent structures. CT scanning can also be used to detect the presence of multiple tumors and can provide evidence of metastatic spread.

Ghanem and colleagues described the CT characteristics of GISTs on the basis of size, as follows[1] :

  • Small (< 5 cm): Sharply demarcated, homogeneous masses, mainly exhibiting intraluminal growth patterns
  • Intermediate (5-10 cm): Irregular shape, heterogeneous density, an intraluminal and extraluminal growth pattern, and signs of biological aggression, sometimes including adjacent organ infiltration
  • Large (>10 cm): Irregular margins, heterogeneous densities, locally aggressive behavior, and distant and peritoneal metastases

In patients with gastric GISTS, the gastric mass can be detected originating from the gastric wall, as depicted in the image below. In some cases, however, the organ site of origin is not clear on CT scan. CT scanning can also be used to evaluate tumor invasion to adjacent structures and the presence of intra-abdominal metastasis. The identification of distant disease is important, as many as half of patients who initially present with a GIST have distant metastases (two-thirds of those have hepatic involvement).

CT scan of the abdomen with oral contrast in a 60- CT scan of the abdomen with oral contrast in a 60-year-old woman with a gastric gastrointestinal stromal tumor (GIST). 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).

Magnetic resonance imaging

Like CT scanning, MRI can depict the tumor or tumors and provide information about surrounding structures. It can also be used to detect the presence of multiple tumors and metastases.

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.

Positron emission tomography

PET scanning with 2-[F-18]-fluoro-2-deoxy-D-glucose (18-FDG PET) has been recommended for detecting metastatic disease in patients with GISTs. However, it is principally useful for early detection of the tumor response to adjuvant therapies such as imatinib mesylate.[34]

 

Procedures

Endoscopy

Endoscopy is frequently performed early in the workup of patients with GISTs, to evaluate GI bleeding, abdominal pain, or GI obstructive symptoms. However, endoscopy is not generally required in the workup of patients with suggestive lesions on CT.

Endoscopic features of GISTs include the suggestion of a firm, smooth, yellowish submucosal mass displacing the overlying mucosa. Some tumors may be associated with ulceration or bleeding of the overlying mucosa from pressure necrosis. See the image below.

Shown here is a gastric gastrointestinal stromal t Shown here is a gastric gastrointestinal stromal tumor (GIST). This is a gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration.

These tumors can be missed on endoscopy because of their frequent submucosal and extraluminal growth. If the diagnosis is suspected prior to endoscopy, an endoscopic ultrasound scan can be performed to further characterize and help confirm the origin of the lesion (when the organ site of the tumor is not clearly evident on CT scan), even if not visible endoscopically.

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) can be a valuable tool in the diagnosis and preoperative assessment of gastric GISTs when the diagnosis or location is in doubt, and EUS is generally the preferred modality to facilitate biopsy of the lesion, when biopsy is indicated. However, EUS is not generally required for preoperative workup.[3, 35]

If the location of the lesion is in doubt, the EUS can help plan the operative approach (eg, demonstrating that a proximal gastric lesion on CT scan is far enough away from the gastroesophageal junction to allow local wedge resection as opposed to total gastrectomy). EUS can also demonstrate the submucosal location of the tumor and can define its size, borders, and echoic pattern.

In general, ultrasonic features of a mass suspicious for malignancy are as follows:

  • Large size
  • Irregular extraluminal borders
  • Presence of cystic spaces and echogenic foci

Preoperative biopsy

While the diagnosis can often be made using ultrasonography-guided biopsy, the use of biopsy is controversial in an otherwise primary, resectable lesion suspicious for GIST. Generally, biopsy is not recommended in this setting.[36] Biopsy of a GIST, which tends to be soft and fragile, may cause intratumoral hemorrhage or even rupture and may increase the risk for tumor dissemination. Irrespective of the biopsy results, surgical resection is typically required for treatment and for definitive diagnosis.

However, biopsy is required in the setting of suspected metastatic disease or when neoadjuvant treatment of a borderline resectable GIST is being entertained. Biopsy may also be important when the diagnosis of GIST in is question, such as when the submucosal nature of the tumor is in doubt or when the tumor shows atypical characteristics on endoscopy or endoscopic ultrasonography. In specific patients, such as those at high operative risk with small benign-appearing lesions and minimal or no symptoms, tissue diagnosis may guide decision making.

Endoscopic biopsy is the recommended procedure for obtaining a preoperative histologic diagnosis. Endoscopic biopsy with ultrasound guidance can achieve a correct histologic diagnosis in more than 80% of cases. Without ultrasound guidance, endoscopic biopsy leads to a correct diagnosis in less than 50% of patients; unguided biopsies may miss the tumor and show only mucosal tissue, or provide samples that contain too little tumor tissue to establish whether the tumor is malignant.

Biopsy specimens can also be obtained percutaneously under CT or ultrasonographic guidance.[37] Consider this approach in selected patients when endoscopic biopsy is impossible to perform or the results are negative.

Histologic Findings

Cellular morphology as visualized by light microscopy can be variable. Most often, the tumors are highly cellular and composed of spindle-shaped cells that resemble smooth-muscle tissue, as depicted in the first image below. However, this histologic appearance is not uniform. A similar tumor with a predominant epithelioid component was historically diagnosed as leiomyoblastoma, as depicted in the second image below. This variant is occasionally associated with a well-defined condition called Carney syndrome.

Photomicrograph of gastrointestinal stromal tumor Photomicrograph of gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 40X. Note the solid sheet of spindle cells.
Photomicrograph of gastric gastrointestinal stroma Photomicrograph of gastric gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 400X. This stromal tumor demonstrates spindle cells with epithelioid features.

Important histologic factors to consider in evaluating these tumors are as follows:

  • Mitotic index
  • Cellularity
  • Necrosis
  • Nuclear atypia and nuclear-cytoplasmic ratio
  • Cell shape
  • Amount of stroma
  • Vascularity

Investigations of GISTs by immunohistochemistry and electron microscopy (ultrastructural parameters) reveal phenotype variability that includes myoid, neural, and indeterminate characteristics.[38] Study of GISTs by immunohistochemistry methods reveals expression of CD117 and other various antigens, such as the following:

  • Nestin (90-100% positivity)
  • CD34 (70% positivity)
  • CD44 [39]
  • Vimentin
  • Desmin
  • Muscle-specific actin
  • Smooth-muscle actin
  • S-100 protein
  • Neurofilament
  • Neuron-specific enolase
  • Protein gene product 9.5 (PGP9.5)

CD117 plays an important role in the latest specific diagnostic criteria for GISTs. CD117 (c-kit protein) is a growth factor receptor with tyrosine-kinase activity and is a product of the proto-oncogene c-kit. CD117, although not tumor-specific, is expressed in all GISTs but not in true smooth muscle tumors and neural tumors.

CD117 has become a very important tool in the differentiation of GIST from other GI mesenchymal tumors.[40, 41] Positive CD117 staining in a spindle-shaped cell GI tumor is diagnostic for GIST, as depicted in the image below. CD34 is another important diagnostic marker. It is detected in approximately 70% of GISTs, and its presence may indicate a higher probability for a malignant phenotype. CD44 is variably expressed by GISTs, but its expression has been demonstrated to correlate with a better prognosis.

Staging

No consensus has been reached regarding a uniform staging system, and none of the currently used classifications is fully satisfactory. Most staging systems employ the three most important survival predictors: tumor size, histologic grade, and presence or absence of distant metastatic disease.

The criteria for risk stratification of primary GIST have been incorporated into the American Joint Committee on Cancer (AJCC) staging seen below. A study by Rutkowski et al found that the AJCC risk classification after resection of primary GIST is reliable in terms of disease-free survival and overall survival.[42] The study concluded that patients with primary gastric GISTs had better prognosis than those with nongastric GISTs. Primary tumor size and mitotic activity were the most important prognostic factors in terms of disease-free survival in both groups.

The stratification is by mitotic index (≤5 or >5 per 50 HPF) and then further divided by tumor size, nodal disease, and tumor metastasis.[43] Risk of progressive disease in GISTs larger than 10 cm but with a mitotic index of ≤5/50 HPF is 10% for gastric GISTs, but 34-57% for GISTs in other locations. For GISTs larger than 10 cm and a high mitotic index (>5/50 HPF), risk of progressive disease is equally high (86%) regardless of tumor location.

Many studies have shown that tumor diameter greater than 5 cm is associated with increased risk for malignancy. However, relation of size to malignant potential may be gradual, with no clear cut-off point.

A high mitotic index (>5/50 HPF usually signifies highly malignant disease. However, a low mitotic index is not always associated with benign course. As many as 25% of tumors with mitotic index of < 5/50 HPF may manifest an aggressive biological behavior. Other histologic parameters, such as cellularity, atypia, and necrosis, are also taken into consideration.

TNM classification

The TNM classification for GISTs is provided in Table 1, below.

Table 1. TNM Classification for Gastrointestinal Stromal Tumors (Open Table in a new window)

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor smaller than 2 cm, localized

T2

Tumor 2-5 cm

T3

Tumor 5-10 cm

T4

Tumor rupture more than 10 cm in greatest dimension

Regional lymph node (N)

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

Metastasis (M)

M0

No distant metastasis

M1

Distant metastases

The staging system for malignant GISTs is shown in Table 2, below.

Table 2. Staging System for Malignant Gastrointestinal Stromal Tumors   (Open Table in a new window)

Group

Tumor Size

Regional Lymph Node

Metastasis

Mitosis

Stage IA

T1 or T2

N0

M0

Low

Stage IB

T3

N0

M0

High

 

T1

N0

N0

High

Stage II

T2

N0

M0

High

 

T4

N0

M0

Low

Stage IIIA

T3

N0

M0

High

Stage IIIB

T4

N0

M0

High

 

Any T

N1

M0

Any rate

Stage IV

Any T

Any N

M1

Any rate

 

Treatment

Medical Care

Although surgical resection is the treatment of choice for gastrointestinal stromal tumors (GISTs) and offers the only chance for cure, the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) plays a major role.[4, 36, 44, 45] The uses of imatinib include the following[36] :

  • Treatment of GISTS that are unresectable, metastatic, or both
  • Preoperative treatment of GISTs that are resectable with negative margins but with risk of significant morbidity
  • Adjuvant treatment following complete gross resection of GIST, to reduce recurrence

The use of imatinib can be guided by genotyping of KIT and PDGFRA mutations.[29, 46] Imatinib shows the highest activity in GISTs that contain the mutation in exon 11 of KIT; approximately 90% of those patients respond. KIT exon 9 Ala502_Tyr503dup mutations, which occur predominantly in intestinal GISTs, are less sensitive to imatinib; approximately 50% respond. To improve response in these patients, a recommended regimen is to initiate imatinib at the standard dose of 400 mg daily and then escalate to 800 mg daily, if tolerated, over approximately 1 month.[47]

GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib.

Most GISTs with PDGFRA gene mutations respond, with the notable exception of those with D842V.[36] There is consensus that patients whose GISTs have the PDGFRA D842V mutation should not be treated with any adjuvant therapy, given the lack of sensitivity of this genotype[29]

Imatinib comes in 100-mg tablets and can thus be given in graduated doses (100, 200, 300, 400, 500, 600, 700, 800 mg) while monitoring treatment responses. The adverse reactions of imatinib are manageable and include edema, rash, diarrhea, nausea, abdominal pain, and fatigue. Treatment interruption or dose reduction may be necessary in patients who develop severe hepatotoxicity or other severe adverse reactions.

In patients who have had their dose reduced due to severe toxicities, responses have been observed with a dose as low as 100 mg. Importantly, clinical trials have determined the efficacy of commonly prescribed doses (400, 600, and 800 mg). In general, doses below 300 mg should be avoided. The maximum tolerated dose of imatinib is 800 mg/d.

The standard dose of imatinib is 400 mg by mouth daily. The prescribed dose should be taken with a low-fat meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

In patients who received imatinib preoperatively and whose GIST was completely resected, the National Comprehensive Cancer Network recommends considering continuation of imatinib postoperatively. Although the duration of imatinib use in this setting has not been studied in randomized trials, data support continuation for 2 years postoperatively.[36]

The use of imatinib as adjuvant therapy to prevent recurrence of primary GIST was approved by the US Food and Drug Administration (FDA) in 2008.[4, 48] In January 2012, the FDA extended the approved duration of use from 1 year to 3 years following surgical removal of CD117-positive GISTs. The approval was based on a randomized study in 400 patients with KIT (CD117)–positive GISTs, which found that at the median 5-year follow-up, overall survival was greater in patients treated for 3 years than in those treated for 1 year (92% vs 82%; hazard ratio [HR], 0.45; P = 0.019); 5-year relapse-free survival was also significantly superior (65.6% vs 47.9%; HR, 0.46; P< 0.0001).[49]

The European Society for Medical Oncology (ESMO) advises that evaluation of response to treatment is complex and that early progression, in particular, should be confirmed by an experienced team. In most cases, anti-tumor activity is indicated by tumor shrinkage but in some, tumor response is indicated only by a decrease in tumor density, or decreased density may precede delayed tumor shrinkage.[29]

Even an increase in the tumor size may indicate tumor response if the tumor density on CT scan is decreased. Even the appearance of seemingly new lesions may be due to pre-existing lesions becoming more evident when they become less dense.[29]

Therefore, ESMO recommends using both tumor size and tumor density on CT scan, or consistent changes in MRI or contrast-enhanced ultrasound, as criteria for tumor response. 2-[F-18]-fluoro-2-deoxy-D-glucose (18-FDG PET) scanning has proved highly sensitive in early assessment of tumor response and may be useful in cases where there is doubt, or when early prediction of the response is particularly useful (eg, preoperative cytoreductive treatments). A small proportion of GISTs have no FDG uptake, however.

The absence of tumor progression after 6 months of treatment also amounts to a tumor response, according to ESMO. On the other hand, tumor progression may occur without changes in the tumor size; such cases may be indicated by increased density within tumor lesions. A typical progression pattern is the “nodule within the mass,” in which a portion of a responding lesion becomes hyperdense.

In the setting of metastatic/advanced GIST, the NCCN recommends continuous use of imatinib until clear evidence of progression occurs. For progressive disease, the imatinib dosage may be increased to 800 mg daily for patients with acceptable performance status (Eastern Cooper ative Oncology Group [ECOG] score 0-2), or therapy may be switched to sunitinib (Sutent), a newer tyrosine kinase inhibitor that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST.

The FDA approved sunitinib in 2006 for the treatment of patients with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib. An interim analysis showed that sunitinib treatment delayed the median time to tumor progression of GISTs to 27 weeks, as compared with 6 weeks for patients who did not receive the drug.

The TKI regorafenib (Stivarga) receive FDA approval in February 2013 for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib. The pivotal phase III trial showed that regorafenib plus best supportive care (BSC) significantly improved progression-free survival (PFS) compared with placebo plus BSC. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo.[50]

In a meta-analysis of three randomized, controlled studies in GIST patients with imatinib resistance or intolerance who received treatment with sunitinib, nilotinib, or regorafenib (n = 541) or placebo/supportive care (n = 267), progression-free survival, but not overall survival, significantly improved in the tyrosine kinase inhibitor treatment group. In patients with resistance or intolerance to both imatinib and sunitinib, treatment with nilotinib or regorafenib improved progression-free, but not overall survival.[51]

Surgical Care

Surgery is the definitive therapy for localized GISTs.[29] Despite the proven success of imatinib and other newer tyrosine kinase inhibitors, surgical resection remains the treatment of choice and offers the only chance for cure from GIST.[52, 53, 54, 55, 56, 57]

The main operative principle is resection of the tumor with negative microscopic margins. Wide resection of the tumor (eg, 2-cm margin) has not been shown to improve outcomes and expert consensus is that dogmatic adherence to a particular width of margin is not necessary or recommended.

For small GISTs, local resection may be adequate, if it is technically possible and 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.[58] 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.

For locally invasive tumors, en bloc resection of adjacent involved organs, such as colon, spleen, or liver, may be indicated. Routine lymphadenectomy is not indicated, as lymph node involvement is very rare.

Recurrence and survival are not associated with the type of resection (wedge resection versus any type of gastrectomy) provided that a complete resection (R0) is performed.

Direct every effort at avoiding tumor rupture during the operation. Tumor rupture is associated with a worse prognosis because of peritoneal seeding.

In cases of disseminated disease, consider palliative resection, because long-term survival has been reported in certain cases. Also consider resection in patients with recurrent disease that manifests as a solitary lesion in the liver or peritoneal cavity. Published reports of liver resection for hepatic metastasis from gastric and other GISTs suggest a survival benefit in selected patients.

Given the ability of imatinib to render initially inoperable GIST tumors resectable,[59] there may be a role for cytoreductive surgery (R0 or R1 resection) in the setting of recurrent metastatic disease confined to the abdomen.[60] Patients should have been on at least 6 months of therapy with imatinib or another tyrosine kinase inhibitor and have had either stable or partially responsive disease during this period.

A significant minority of these patients require liver resections (40%) and the majority require multivisceral resection, including bowel resections, peritonectomy, and/or omentectomy (60%). Even after such aggressive resection, R1 resections (microscopically positive resections) are the rule, R0 resections are rare, and about 5% of patients still have bulky disease remaining.

Up to 70% of patients able to undergo an R0/R1 resection in the setting of stable or partially responsive disease enjoy a progression-free survival as long as 4 years after the initiation of imatinib therapy.[61]

Because adequate resection for small malignant GISTs can be achieved by wedge resection, minimally invasive surgery techniques can be considered in selected cases, such as those in favorable anatomic locations (eg, the greater curvature or anterior wall of the stomach).[36]

Laparoscopic surgery

Laparoscopic resection is increasingly used for treatment of GISTs. A study by Chen et al concluded that laparoscopic surgery was technically possible for GISTs no larger than 5 cm located at the stomach and small bowel. Benefits of laparoscopic resection included faster resumption of a normal diet, shorter postoperative hospital stays, and less analgesia use. Short-term oncology results were the same with laparoscopy as with open surgery.[62]

Numerous published reports of laparoscopic resection of gastric GISTs have demonstrated the feasibility and safety of this technique.[63, 64, 65, 66, 67, 68]  In a retrospective study of 666 patients who underwent primary resection for a gastric GIST smaller than 20 cm, Piessen et al reported that laparoscopic treatment of gastric GISTs was associated with significantly lower overall, surgical, and medical morbidity, and significantly better 5-year recurrence-free survival (RFS). In addition, subgroup analysis of patients with tumors larger than 5 cm found that laparoscopic and open approaches yielded comparable in-hospital morbidity and 5-year RFS.[69]

 

Postoperative care

Depending on the type of resection, a nasogastric tube is left in place postoperatively. Ensuring that the tube is continuously functional and remains unclogged is crucial. Criteria for removal of a nasogastric tube vary by clinician.

A urinary Foley catheter remains in place in the early postoperative period or during the preoperative resuscitative period in patients who have sustained major hemorrhage or other complications. The catheter aids monitoring of hydration status and serves as a guide for fluid resuscitation. Once the patient is stabilized and no additional major fluid shifts are anticipated, the catheter can be removed.

Pulmonary toilet

Instruct patients to cough and to take frequent deep breaths. The incentive spirometer is an important adjunct for this and should be used by the patient every 1-2 hours while awake. Early mobilization of the patient assists with maintaining good pulmonary toilet.

Monitoring

Vital signs are monitored per protocol. Intake and output records are kept. Pulse oximetry is used when appropriate to measure oxygen saturation.

Antibiotics

Unless bowel perforation or other septic complications have occurred, a single dose of intravenous antibiotic prophylaxis against wound infection is usually sufficient.

Patients with abdominal catastrophes such as bowel perforation or infarction require a full therapeutic course of intravenous antibiotics that cover the spectrum of gut flora.

Pain control, deep venous thrombosis prophylaxis, and aspiration precautions

An epidural catheter can be placed by anesthesia personnel for postoperative pain control. Alternately, a patient-controlled anesthesia schedule can be ordered.

Prophylaxis against deep venous thrombosis is crucial because it and pulmonary embolism are significant sources of postoperative morbidity and mortality. Available modalities include subcutaneous heparin, subcutaneous fractionated heparin preparations, and sequential compression stockings.

The head of the bed can be kept elevated 30-45°, or sometimes higher for elderly patients or during sleep, to help prevent aspiration.

Complications

Complications can be divided into preoperative and postoperative categories. Preoperative tumor-related complications usually occur with tumors larger than 4 cm.

Major preoperative complications include the following:

  • Hemorrhage
  • Bowel obstruction
  • Volvulus
  • Intussusception
  • Bowel perforation with peritonitis

The range of postoperative complications is similar to that for major abdominal and GI surgery. The following is a representative but not exhaustive list:

  • Wound infection
  • Wound dehiscence with or without evisceration
  • Urinary tract infection
  • Atelectasis
  • Pneumonia
  • Anastomotic disruption
  • Anastomotic stricture
  • Marginal ulceration
  • Intra-abdominal abscess formation
  • Cholangitis
  • Delayed gastric emptying or gastroparesis
  • Internal or enterocutaneous fistula
  • Small bowel obstruction
  • Dumping syndrome
  • Alkaline reflux gastritis
  • Cardiac arrhythmias
  • Myocardial infarction
  • Deep venous thrombosis
  • Pulmonary embolism

Consultations

The management of GISTs requires the participation of a multidisciplinary team. The team should include a surgeon, gastroenterologist, and medical oncologist.

Diet

Postoperatively, patients receive nothing by mouth for varying durations, depending on the preference of the operating surgeon. Following nasogastric tube removal, patients can be started on a liquid diet and advanced to a full diet as tolerated. Postgastrectomy diet counseling by a registered dietitian is helpful in patients undergoing subtotal or total gastrectomies.

Depending on the patient's preoperative nutritional status, a period of specialized nutritional support might be indicated. This can range from enteral tube feedings to peripheral hyperalimentation to total parenteral nutrition. Multivitamin and iron supplementation may be indicated.

 

Guidelines

Guidelines Summary

Genetic Testing

The National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Panel specifically identifies Carney-Stratakis syndrome as associated with gastrointestinal stromal tumors (GISTs). NCCN recommends that in patients with GIST lacking KIT or PDGFRA mutations, SDH gene mutational analysis should be considered; loss of SDHB protein expression by immunohistochemistry is a useful screen to identify patients who would be candidates for germline mutation testing, but it is not diagnostic of a germline mutation.[36]

WHO Classification of Tumors

In 2013 the World Health Organization released an update of its 2002 classification system for tumors of the soft tissue and bone.  The update incorporated more detailed cytogenetic and molecular data into the classifications. Gastrointestinal stromal tumors (GISTs) have been added in the update, with three subtypes[70] :

  • Benign
  • Uncertain malignant potential
  • Malignant

Tumor Grading Systems

The French Federation of Cancer Centers Sarcoma Group (FNCLCC) system [71] and the National Cancer Institute system are most commonly used for grading soft tissue sarcomas.6 Both are three-grade systems.[72] The FNCLCC is based on tumor differentiation, tumor necrosis and mitotic activity, while the NCI system bases the evaluation on histology, location and tumor necrosis. In comparison studies, the FNCLCC has shown slightly better ability to predict metastasis development and mortality.

Tumor Staging

Both NCCN and the European Society for Medical Oncology (ESMO) guidelines follow the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) for staging of GISTs. Gastrointestinal stromal tumors (GIST) are staged separately from other sarcomas, with tumors graded as low or high. Anatomic stage/prognostic groupings for GIST are detailed in Table 1, below.[73]

Table 1. Staging of Gastrointestinal Stromal Tumors (Open Table in a new window)

Stage

T

N

M

Grade

IA

T1 or T2

N0

M0

Low

IB

T3

N0

M0

Low

II

T1

N0

M0

High

T2

N0

M0

High

T4

N0

M0

Low

IIIA

T3

N0

M0

High

IIIB

T4

N0

M0

High

IV

Any T

N1

M0

Any grade

Any T

Any N

M1

Any grade

For description of GIST TNM designations, see Gastrointestinal Stromal Tumors Staging.

Diagnosis

The NCCN guidelines for gastrointestinal stromal tumors (GISTs) recommend evaluation and management, prior to initiation of therapy, by a multidisciplinary team with expertise and experience in sarcoma. Abdominal/pelvic CT scan with contrast, with or without MRI, is also indicated and chest imaging should be considered. Very small GISTS (< 2 cm) may be evaluated with endoscopic ultrasound-guided fine-needle aspiration; for GISTS 2 cm or larger, endoscopy with or without ultrasound may also be indicated in select patients.[36]

Genetic testing for KIT and PDGFRA is a strong recommendation, and in the absence of KIT or PDGFRA mutations, testing for loss of SDHB protein expression by immunohistochemistry should be considered.  If SDHB expression is lost, then genetic counseling and germline mutation testing in SDH genes should be considered. In patients with advanced GISTs, identification of certain specific KIT and PDGFRA mutations helps predict responsiveness to imatinib and the possible benefit of a higher imatinib dose.[36]

ESMO guidelines recommend that patients with small esophagogastric or duodenal nodules < 2 cm undergo endoscopic ultrasound assessment and then annual follow-up, reserving excision for patients whose tumor increases in size or becomes symptomatic. For small rectal nodules, however, the ESMO guidelines recommend biopsy/excision after ultrasound assessment, regardless of tumor size. In addition, all nodules 2 cm or larger require biopsy.[29]

Treatment

NCCN treatment recommendations for localized resectable disease include the following[36] :

  • Surgical resection is the primary treatment; for tumors < 2 cm with no high-risk features, consider endoscopic surveillance at 6-12 month intervals
  • Preoperative treatment with imatinib may prevent accurate assessment of recurrence risk; consider preoperative imatinib only if surgical morbidity could be reduced by downstaging the tumor preoperatively
  • Testing the tumor to ensure it has a genotype that is likely to respond to imatinib (especially  KIT exon 11) is recommended prior to starting preoperative imatinib
  • Consider postoperative imatinib for at least 36 months  for high-risk tumors

ESMO guidelines discourage a laparoscopic approach for resection of large tumors.[29]

NCCN treatment recommendations for unresectable or metastatic disease include the following[36] :

  • Imatinib (category 1)
  • After assessment of therapeutic effect, resection may be considered or imatinib may be continued if resection is not feasible
  • Continuous daily dosing of sunitinib for patients with imatinib-resistant GIST
  • Regorafenib (category 1) for patients with disease progression on imatinib and sunitinib
  • Tyrosine kinase inhibitor (TKI) therapy should be continued as long as patients are receiving clinical benefit (response or stable disease)
  • Continuation of TKI therapy lifelong for palliation of symptoms is an essential component of best supportive care
 

Medication

Medication Summary

The goals of pharmacotherapy in patients with gastrointestinal stromal tumors (GISTs) are to induce remission, reduce morbidity, and prevent complications. The tyrosine kinase inhibitor (TKI) imatinib is used in unresectable GISTs and metastatic malignant GISTs, and as adjuvant treatment following complete gross resection of GISTs. The TKIs sunitinib and regorafenib are used for GISTS that become unresponsive to imatinib.

Antineoplastics, Tyrosine Kinase Inhibitor

Class Summary

Agents with strong tyrosine-kinase inhibition activity of the bcr-abl abnormality in all cell-cycle phases of gastric tumor cells.

Imatinib mesylate (Gleevec)

Specifically designed to inhibit tyrosine-kinase activity of the bcr-abl kinase in GI stromal tumors. These tumors are characterized by expression of the product of the proto-oncogene c-kit and often harbor gain-of-function KIT mutations, leading to ligand-independent kinase activation. Gleevec inhibits ABL, KIT, and PDGFR tyrosine kinase.

Sunitinib malate (SU-11248, Sutent)

Multikinase inhibitor that targets several tyrosine-kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).

Indicated for persons with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib (Gleevec). Delays median time to tumor progression.

Regorafenib (Stivarga)

Regorafenib is a tyrosine kinase inhibitor. It is indicated for locally advanced, unresectable gastrointestinal stromal tumors that no longer respond to other treatments (eg, imatinib, sunitinib).

 

Follow-up

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 tyrosine kinase inhibitors for unresectable and/or metastatic disease. Follow-up includes physical examination and computed tomography (CT) scanning, and possibly periodical gastroscopies, as well.

For followup of gastric GISTs < 2 cm that have been completely resected, the National Comprehensive Cancer Network (NCCN) recommendations vary according to the presence or absence of high-risk features (eg, irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity). For GISTs with high-risk features, the NCCN recommends considering abdominal/pelvic CT with contrast every 3-6 months for 3-5 years, then annually. For those without high-risk features, endoscopic surveillance at 6-12 month intervals may be considered.[36]

For followup of patients with metastic or persistent gross residual disease, the NCCN recommends followup with history and physical examination and abdominal/pelvic CT every 3-6 months. For patients with completely resected GISTs, the NCCN recommends history and physical examination every 3-6 months for 5 years, then annually, plus abdominal/pelvic CT every 3-6 months for 35 years, then annually.[36]

Prognosis

GISTs manifest a wide variety of clinical behavior, from slow-growing indolent tumors to aggressive malignant cancers with the propensity to invade adjacent organs, metastasize to the liver, and recur locally within the abdomen. Clinical presentation provides the most overt evidence for distinguishing benign from malignant behavior. Histologic analysis of biopsy or operative specimens provides objective measures for diagnosis and helps predict clinical behavior.

The predominant prognostic factors in patients with GISTs include the size of the tumor, location of the tumor, and the mitotic rate.[74, 75, 76] To these may be added the ability or inability to achieve completely negative resection margins. The following characteristics appear to be the most predictive of aggressive behavior in GISTs:

  • Mitotic rate greater than 5 mitoses per 50 high-power fields (HPFs)
  • Size larger than 5 cm and 10 cm, which pose moderate and high malignant potential, respectively [16]
  • Location (small bowel GISTs of comparable size and mitotic rate are generally more aggressive than gastric GISTs)

Because no standardized staging system exists for stromal tumors of the GI tract and most series are small and heterogeneous, comparison of the different published survival rates is difficult. However, various reports of 5-year survival rates after R0 resection for GISTs range from 32-93%. In large series, this rate is about 50-60%.

The median survival after palliative resection is about 10 months, with a 5-year survival rate as high as 10%. These rates improve with the addition of imatinib.[68, 69, 74, 75] The disparity between patients presenting with localized primary disease (median survival of 5 y) and those presenting with metastasis or recurrent disease (median survival of 10-20 mo) is large.

Unfortunately, no absolute determinations can be made because even small lesions with low mitotic rates can metastasize or behave in a locally aggressive fashion. In 2002, Fletcher and colleagues proposed the following classification system to define the risk of aggressive or malignant behavior in GISTs[77] :

  • Very low risk: size < 2 cm and < 5 mitoses/50 HPFs
  • Low risk: 2-5 cm and < 5/50 HPFs
  • Intermediate risk: < 5 cm and 6-10/50 HPFs or 5-10 cm and < 5/50 HPFs
  • High risk: >5 cm and >5/50 HPFs or   >10 cm and any mitotic rate or any size and >10/50 HPFs

In 2009 Gold et al from Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram that uses tumor size, site, and mitotic index to predict relapse-free survival after resection of localized primary GIST.[78]

The NCCN criteria for risk stratification of primary GIST have not been incorporated into the AJCC staging but may be more helpful in determining individual risk for progressive disease, after margin-negative resection.[36] The stratification is by mitotic index (≤5 versus >5 per 50 HPF) and then further divided by tumor size (≤2 cm vs >2 cm; ≤5 cm vs >5 cm; ≤10 cm vs >10 cm) and tumor location (gastric, duodenum, jejunum-ileum, and rectum).

Gastric GISTs greater than 10 cm but less than or equal to 5/50 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 (>5/50 HPFs), however, have an equally high risk of progressive disease (86%) as GISTs in other locations.

Mutational status has both prognostic significance and impact on response to tyrosine kinase inhibitor therapy. In randomized clinical trials, the presence of a KIT exon 11 mutation was associated with better response, progression-free survival, and overall survival rates than KIT exon 9 mutant GISTs. The risk for progression and death were increased in patients with no detectable KIT or PDG-FRA mutations.[11]

Other factors found to have a negative impact on prognosis are as follows:

  • Tumor rupture during operation
  • Involvement of histologic margins
  • Lymph node involvement

In an analysis of 4,694 patients with localized GISTs from the National Cancer Data Base, Sineshaw and colleagues found that patients treated with adjuvant therapy had a 46% lower risk of death than patients treated with surgery alone, This survival benefit was significant for patients with GISTs larger than 10 cm.[79]

Patient Education

Patients should be educated about as many aspects of the disease as possible, including diagnostic and therapeutic measures and options. GIST Support International has produced a patient education booklet entitled Understanding Your GIST Pathology Report.

Most importantly, patients should be apprised of the need for lifelong close clinical follow-up, even after complete resection of disease. Emphasize that GISTs have a propensity to recur.

For patient education resources, see the Cancer Center.