eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Gastric Gastrointestinal Stromal Tumors

Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine

Updated: Jun 4, 2009

Introduction

Background

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the gastrointestinal (GI) tract and are thought to develop from the interstitial cells of Cajal, innervated cells associated with the Auerbach plexus. GISTs are typically defined by the expression of c-KIT (CD117) in the tumor cells, as these activating KIT mutations are seen in 85-95% of GISTs. About 3-5% of the remainder of KIT -negative GISTs contain PDGFR alpha mutations.^1,2,3

The PDGFR alpha mutation seems to leave the PDGFR a-receptor constitutively active and may represent an alternate pathway with activation of similar downstream signaling as the KIT receptor. The recent discovery of these receptor mutations has redefined the classification and management of the disease. With only about 5000 new cases expected annually in the United States, GISTs are rare and constitute only 1% of all malignant tumors of the GI tract but are the most common mesenchymal neoplasm of the GI tract.

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.

Histologically, GISTs can be distinguished from cellular spindle cell (70%) tumors to epithelioid (20%) or pleomorphic/mixed morphology tumors, but such histologic distinction does not carry clear prognostic significance. While GISTs are typically CD117-positive (85-95%), positivity for CD34 (60-70%), nestin, ACAT2, S100 (10%), and DES may be helpful in establishing the diagnosis.

Characteristics of GISTs that are predictive of aggressive behavior are mitotic rate greater than 5 per 10 high-power fields (HPF), size larger than 5 cm and 10 cm, and location (small bowel GISTs of comparable size and mitotic rate are generally more aggressive than gastric GISTs). However, tumors with low mitotic index (<5 per 50 HPF) and smaller size (2-5 cm) can also metastasize. So while gastric GISTs are commonly less aggressive than those of nongastric intestinal origin, they still maintain the propensity for distant spread.

Pathophysiology

GISTs are typically diagnosed as solitary lesions, although in rare cases, multiple lesions can be found. These tumors 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.

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.

Frequency

United States

An estimated 5000 new cases are diagnosed annually in the United States, as compared to about 150,000 new cases of colorectal cancer.

International

GISTs are rare, and data concerning its worldwide prevalence are lacking. In general, it constitutes 1-3% of all gastric malignancies.

Mortality/Morbidity

Long-term survival is typically correlated inversely with tumor size and mitotic rate. 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%.

Patients with advanced GIST on tyrosine-kinase inhibitor therapy may develop tumor-related intraluminal or intraperitoneal hemorrhage, rupture, fistula, or obstruction requiring emergent surgery.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

Onset can occur at any age but occurs most commonly in the sixth and seventh decades of life.

Clinical

History

• Upper GI bleeding is the most common clinical manifestation of gastrointestinal stromal tumors (GISTs), manifesting as hematemesis or melena in 40-65% of patients. Bleeding occurs because of an ulcer forming in the gastric mucosa overlying the tumor.
• Other symptoms are generally associated with an enlarging abdominal mass and may include abdominal pain, anorexia, nausea, vomiting, weight loss, epigastric fullness, and early satiety.
• Not uncommonly, GISTs can be found incidentally, at endoscopy or even at the time of surgery. In Japan, mass screening for gastric adenocarcinoma with upper endoscopy has led to an increase in incidental findings of asymptomatic GISTs.

Physical

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

Causes

No risk factors have been identified.¹²

Differential Diagnoses

Gastric Cancer
Gastrointestinal Stromal Tumors

Other Problems to Be Considered

Gastric schwannoma
True smooth muscle tumor of the stomach (leiomyoma)
Gastric sarcoma
Gastric adenocarcinoma

The differential diagnosis for gastric stromal tumors includes benign lesions such as true leiomyoma, schwannoma, lipoma, ectopic pancreas, and sarcomas.¹³

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.

Workup

Laboratory Studies

Laboratory studies are not diagnostic, and no identifiable tumor markers exist.

Imaging Studies

• Computed tomography scanning of the abdomen: Abdominal CT scanning with intravenous and oral contrast material is a necessary step in the evaluation of these patients. The gastric mass can be detected originating from the gastric wall (see Image 2), but, at times, 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 whom have hepatic involvement).
  
  

  

  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).

  
  
• 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 but is not generally required for preoperative workup.^14,15
  • 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 GE 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 large tumors, tumors with irregular extraluminal borders, and the presence of cystic spaces and echogenic foci.
  • All gastric GISTs should be considered to have malignant potential. Although, generally, gastric GISTs less than 2 cm tend to behave as "benign" masses, there have been rare reports of distant spread. EUS is generally the preferred modality to facilitate biopsy of the lesion in cases in which biopsy aids in the workup and management of the patient (see Preoperative biopsy).

Procedures

• Upper endoscopy: Upper endoscopy is often the first examination performed in the evaluation of patients with upper gastrointestinal symptoms, but endoscopy is not generally required in the workup of patients with lesions on CT suspicious for a gastric GIST. Gastroscopy may demonstrate a firm, smooth, yellowish submucosal mass, which can be ulcerated (see Image 1). These tumors can be missed endoscopically because of their frequent submucosal and extraluminal growth. If the diagnosis is suspected prior to endoscopy, an endoscopic ultrasound can be performed to further characterize and help confirm the lesion's growth from the stomach (when the organ site of the tumor is not clearly evident on CT scan), even if not visible endoscopically.
  
  

  

  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.

  
  
• Preoperative biopsy: While the diagnosis can often be made using ultrasonographic-guided biopsy, the use of biopsy is controversial in an otherwise primary, resectable lesion suspicious for GIST.

• Generally, unless a concern for an alternative diagnosis or use of neoadjuvant therapy is being entertained, the use of biopsy is not recommended in this setting (www.nccn.org).¹⁶ The 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. Generally, irrespective of the biopsy results, surgical resection is required for treatment and for definitive diagnosis. 
• Reasons to perform a biopsy: A biopsy is important and required in the setting of suspected metastatic disease or when neoadjuvant treatment of borderline resectable GIST is being entertained.
  • The initial treatment of metastatic GIST should generally be tyrosine-kinase inhibitor therapy with imatinib. Patients with GISTs that appear to involve critical structures or are in challenging locations (eg, duodenal requiring Whipple) may benefit from neoadjuvant therapy. Prior to initiation of imatinib for either metastatic disease or in the neoadjuvant setting, a pretreatment biopsy is generally required to confirm the diagnosis prior to initiation of such treatment. 
  • Biopsy may also be important when the diagnosis of GIST in is question, such as when the submucosal nature of this tumor is in doubt or when tumor characteristics as demonstrated by upper endoscopy and endoscopic ultrasonography are not typical. In specific patients, such as high-risk operative patients with small benign-appearing lesions and minimal or no symptoms, tissue diagnosis may help in further decision-making.
• The 2 ways to obtain a preoperative histologic diagnosis are as follows:
  • Endoscopic biopsy: Preoperative endoscopic biopsy may be taken with or without EUS guidance. When taken without the help of EUS, endoscopic biopsy is not accurate and leads to a correct diagnosis in less than 50% of patients. Biopsies may miss the tumor and show only mucosal tissue. In addition, samples from the tumor itself are often too small to establish malignant nature. EUS-guided biopsy is more accurate. This technique can achieve a correct histologic diagnosis in more than 80% of cases and should be performed whenever preoperative histology seems necessary.
  • Percutaneous biopsy: Tumor biopsy can be obtained percutaneously under CT scanning or ultrasonographic guidance.¹⁷ Consider this procedure in selected patients when endoscopic biopsy is impossible to perform or the results are negative.

Histologic Findings

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 stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 400X. This stromal tumor demonstrates spindle cells with epithelioid features.

Investigations of GISTs by immunohistochemistry and electron microscopy (ultrastructural parameters) reveal phenotype variability that includes myoid, neural, and indeterminate characteristics.¹⁸ Study of GISTs by immunohistochemistry methods reveals expression of CD117 and other various antigens, such as nestin (90-100% positivity), CD34 (70% positivity), CD44,¹⁹ vimentin, desmin, muscle-specific actin, smooth-muscle actin, S-100 protein, neurofilament, neuron-specific enolase, and 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.^20,21 Positive CD117 staining in a spindle-shaped cell GI tumor is diagnostic for GIST (see Image 5). 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.

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.

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 3 most important survival predictors—tumor size, histologic grade, and presence or absence of distant metastatic disease.

The NCCN criteria for risk stratification of primary GIST have not been incorporated into the AJCC staging seen below but may be more helpful in determining individual risk for progressive disease.¹⁶ The stratification is by mitotic index (5 or less or more than 5 per 50 HPF) and then further divided by tumor size (2 cm or less or more than 2 cm; 5 cm or less or more than 5; 10 cm or less or more than 10 cm) and tumor location (gastric, duodenum, jejunum-ileum, and rectum). 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, relation 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 benign course. As many as 25% of tumors with mitotic index of less than 5 mitoses per 10 HPF may manifest an aggressive biological behavior. Some authors have defined an intermediate-risk category applied for tumors with a mitotic index of 2-4 mitoses per 10 HPF.

• Tumor size
  • T1- Tumor smaller than 5 cm, localized
  • T2 - Tumor 5 cm or larger, localized
  • T3 - Contiguous organ invasion or peritoneal implants
  • T4 - Tumor rupture
• Tumor grade
  • G1- Low grade
  • G2 - High grade
• Metastasis
• M0 - No metastasis
• M1 - Distant metastases Table 1. Proposed Staging System for Malignant Gastrointestinal Stromal Tumors

  Stage	Tumor Size	Tumor Grade	Metastasis
  Stage I	T1	G1	M0
  Stage II	T2	G1	M0
  Stage III	T1-2 T3	G2 Any G	M0 M0
  Stage IVa	…	…	M1 or residual disease after surgery
  Stage IVb	T4	…	…

Treatment

Medical Care

Current data suggest a major role for the tyrosine-kinase inhibitor, imatinib mesylate (STI-571, Gleevec), for patients with GISTs.^10,22,23 Despite such a major role, no standard regimen for adjuvant therapy presently exists for GISTs. The optimal duration of treatment with imatinib remains unknown and observation after margin-negative resection of primary GIST remains acceptable. While recurrence-free and progression-free survival have clearly been increased with the use of imatinib in both the adjuvant and advanced/metastatic settings, overall survival has not been proven to be improved in either setting.
 
On December 19, 2008, the Food and Drug Administration (FDA) approved imatinib mesylate as adjuvant therapy to prevent recurrence of primary GIST. This FDA approval was based on the phase III double-blind placebo-controlled randomized controlled multicenter trial ACOSOG Z9001, which revealed a 97% versus 83% 1-year recurrence-free survival benefit to imanitib.^10,24 This trial enrolled patients with 3 cm or greater KIT -positive GIST who were treated with imatinib or placebo for one year; the trial results did not stratify by mitotic rate or tumor location. 

The current recommendation by the NCCN (www.nccn.org) is to consider prescribing imatinib in the adjuvant setting in any patient with intermediate-risk or high-risk GIST and to treat for at least 12 months (given the design of the Z9001 trial, see above).¹⁶ In the metastatic/advanced setting, the NCCN recommends continuous use of imatinib until clear evidence of progression. For progressive disease, the dose of imatinib may be increased for patients with acceptable performance status (ECOG 0-2) or therapy may be switched to sunitinib. Sunitinib is a newer tyrosine-kinase inhibitor that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST.

• Initially, numerous trials confirmed the activity of imatinib in metastatic or advanced GIST, demonstrating substantial tumor responses in such patients.
  • As the result of these substantial tumor responses in several trials, the Food and Drug Administration (FDA) approved imatinib mesylate for metastatic GIST on February 1, 2002. This approval occurred under accelerated approval regulations and under the orphan drug program. The orphan drug program provides financial incentives for drugs developed to treat rare diseases (ie, diseases that affect <200,000 patients).
  • Imatinib was used in patients with chronic myeloid leukemia (CML). CML is characterized by a balanced translocation between chromosomes 9 and 22 (the Philadelphia chromosome) and this abnormality results in the production of the BCR-ABL fusion protein. This BCR-ABL protein has uncontrolled tyrosine-kinase activity and imatinib was found to induce a near-complete response in virtually all patients treated in the chronic phase of CML. In 2001, a New England Journal of Medicine case report of a patient with rapidly progressive metastatic GIST who had a dramatic response to imatinib started the targeted therapy revolution of GIST.²²
  • The initial approval of imatinib for the treatment of GIST was based upon a study of 147 patients with unresectable or metastatic GIST who received daily oral imatinib. While no patient had complete disappearance of tumor, 56 patients (38%) had reduction in tumor size by 50% or greater (partial response).
  • The subsequent development of imatinib mesylate has revolutionized the treatment of GISTs. After numerous clinical trials, 55-80% of patients with metastatic GIST achieve a partial response or stable disease while receiving imatinib. The adverse reactions of imatinib are manageable and include edema, rash, diarrhea, nausea, abdominal pain, and fatigue.
  • Currently, the standard dose of imatinib in both adjuvant therapy and in therapy of advance disease is 400 mg by mouth daily.
  • Imatinib shows the highest activity in GISTs who contain the mutation in exon 11 of c-KIT and less activity in GISTs who contain the mutation in exon 9 or who are wild-type. Subset analysis  suggests that patients whose GIST contains exon 9 mutations may benefit from a higher dose of imatinib (? 800 mg daily) then the standard dose (400 mg daily), but this remains to be proven.
    • Phase I clinical trials determined that the maximum tolerated dose (MTD) of imatinib is 800 mg/d. 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. Patients who have had their dose reduced due to severe toxicities have been observed to have a response with a dose as low as 100 mg of imatinib. Importantly, clinical trials have determined the efficacy of commonly prescribed doses (400 mg, 600 mg, and 800 mg). In general, doses below 300 mg should be avoided.
    • In the United States, the FDA recommended starting dosage of imatinib (Gleevec), as of December, 2008, is 400 mg/d for patients with unresectable and/or metastatic, malignant GIST and for patients receiving adjuvant Gleevec. Increasing the dose up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in particular in patients with exon 9 mutations (given the subset analysis that suggested an improved response in this cohort of patients). Clinical indications include clear signs or symptoms of disease progression at a lower dose; dose escalation in this setting is only justified in the absence of severe adverse drug reactions. As the new data on exon 9 response is reviewed, it is possible that the benefit preliminarily attributed to an increased dose of imatinib (800 mg daily divided bid) in these patients may not ultimately be borne out in the final analysis.
    • The prescribed dose should be administered orally, with a 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.
    • Patients who become resistant to imatinib often develop secondary mutations. A 2009 study examined why threonine is always replaced by isoleucine and explained with a combination of in vitro and molecular modeling analyses that only Ile is naturally selected as a resistance mutant in gastrointestinal stromal tumors treated with imatinib.²⁵
• Other agents with tyrosine-kinase inhibitory activity are also showing significant promise for the treatment of GISTs, and especially in the treatment of GISTs with resistance to imatinib. Dasatinib (BMS-354825) is currently being studied in clinical trials.²⁶ In January 2006, the FDA approved sunitinib malate (SU-11248, Sutent) for the treatment of patients with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib. While studying the treatment in patients, sunitinib was shown at interim analysis to delay the median time-to-tumor progression (TTP) of GISTs to 27 weeks as compared with 6 weeks for patients who did not receive the drug.

Surgical Care

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.^{27,28,29,30,31,32} 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 such dogmatic adherence to a particular width of margin is not necessary or recommended.

• For small gastric tumors, wedge resection is adequate, if technically possible.³³ Larger tumors necessitate subtotal or total gastrectomy. Enucleation should be avoided because predicting malignant potential preoperatively is difficult, even in benign-appearing lesions.
• 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, manifested 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.
• In the advent of effective therapy for metastatic GIST disease with imatinib,³⁴ there may be a role for cytoreductive surgery (R0 or R1 resection) in the setting of recurrent metastatic disease confined to the abdomen.³⁵
  • Patients should have been on at least 6 months of tyrosine-kinase inhibitor therapy (eg, imatinib) and have 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.³⁶
• Because adequate resection for small malignant GISTs can be achieved by wedge resection, minimally invasive surgery techniques can be considered in selected cases. In recent years, numerous published reports of laparoscopic resection of gastric GISTs have demonstrated the feasibility and safety of this technique.^{37,38,39,40,41,42,43}

Medication

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

Tyrosine-Kinase Inhibitors

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.

Dosing

Adult

400 mg PO qd with food; may increase to 800 mg/d divided bid in absence of adverse effects for patients with advanced or metastatic GIST who progress through lower 400 mg daily dose; consider higher dose for patients with exon 9 mutations as they might have improved outcome at higher dose

Pediatric

Not established

Interactions

CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastatin increases maximum concentration of imatinib by a 2- to 3.5-fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dose must be reduced if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develop

Multikinase inhibitors

Elicit actions via multiple tyrosine-kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

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.

Dosing

Adult

Standard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle
Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability
Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle
Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle

Pediatric

Not established

Interactions

Potent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently)

Contraindications

Documented hypersensitivity; concurrent administration with St John's wort

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding

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 imatinib mesylate or sunitinib malate for unresectable and/or metastatic disease. Follow-up includes physical examination and periodical gastroscopies as well as CT scanning. Ideal time intervals for performing these studies have not been well established.

Prognosis

• In general, long-term survival for malignant GIST after a curative-intent surgery is strongly related to tumor size, mitotic rate, and tumor location.^44,45,46 Gastric GISTs tend to act less aggressively than small bowel GISTs of comparable size and mitotic rate.
• Because no standardized staging system exists for stromal tumors of the GI tract and most series are small and heterogenous, comparison of the different published survival rates is difficult. However, various reports of 5-year survival rates after R0 resection for gastrointestinal stromal tumors 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.
• 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.¹⁶ The stratification is by mitotic index (5 or less or more than 5 per 50 HPF) and then further divided by tumor size (2 cm or less or more than 2 cm; 5 cm or less or more than 5 cm; 10 cm or less or more than 10 cm) and tumor location (gastric, duodenum, jejunum-ileum, and rectum). Gastric GISTs greater than 10 cm but less than or equal to 5 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.
• Ng et al in 1992 have reported the long-term survival of 139 patients with gastrointestinal malignant stromal tumors from different sites—40% gastric tumors. The overall 5-year survival rates by stage for GI stromal tumors is as follows:⁴⁷
  • Stage I - 75%
  • Stage II - 52%
  • Stage III - 28%
  • Stage IVa - 12%
  • Stage IVb - 7%
• In another large series of patients after resection of malignant GISTs published by Koga et al in 1995, survival was studied according to a classification combining tumor size and mitotic index. A very high survival rate was found in patients with tumors smaller than 6 cm and low mitotic index.⁴⁵ Table 2. Five-Year Survival According to Size and Number of Mitoses

  Size, cm	Mitoses per 20 HPF	5-Year Survival Rate
  <6	<4	97.5%
  >6	<4	91.5%
  <6	>4	80.0%
  >6	>4	17.7%

• Histologic grade alone is a strong prognostic factor. In 1982, Shiu et al reported a 5-year survival rate of 80% in patients after resection of low-grade tumors (low mitotic index, no necrosis). The 5-year survival rate dropped to 32% in patients with high-grade tumors (high mitotic index, regions of necrosis).⁴⁸
• Other factors found to have a negative impact on prognosis are tumor rupture during operation, involvement of histologic margins, and lymph node involvement.
• The liver and the peritoneal cavity represent the predominant sites of recurrence after attempted curative surgery. Extra-abdominal sites (eg, lungs) are less common. Evaluate patients with recurrent disease for possible second resection if feasible. Survival prolongation is reported for resected local recurrences and even for resected isolated hepatic or peritoneal recurrent lesions.

Miscellaneous

Medicolegal 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. While imatinib has been approved as adjuvant therapy for resected GIST, the optimal duration of therapy remains unknown. It is also unclear as to which population of patients should receive adjuvant therapy, as the initial phase III randomized controlled trial stratified outcomes only by size and not mitotic index or tumor location.
• Direct every effort at avoiding tumor rupture during surgical therapy. Tumor rupture is associated with a worse prognosis because of peritoneal seeding.
• Because malignant potential is difficult to determine preoperatively, a wide resection with clear margins is routinely indicated.
• Malignant behavior in low mitotic tumors smaller than 2 cm is rare but is reported.

Multimedia

Media file 1: 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.

Media file 2: 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).

Media file 3: Photomicrograph of gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 40X. Note the solid sheet of spindle cells.

Media file 4: 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.

Media file 5: 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.

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Keywords

gastric gastrointestinal stromal tumors, gastric GISTs, malignant gastric stromal tumors, gastric leiomyosarcomas, gastrointestinal stromal tumors, GISTs, gastric GIST, fibrosarcoma, angiosarcoma, hemangiopericytoma, gastric smooth muscle tumors, intestinal smooth muscle tumors

Contributor Information and Disclosures

Author

Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Michael A Choti, MD, MBA is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American Surgical Association, Association for Academic Surgery, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, and Society of University Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Matthew Hueman, MD, Fellow in Surgical Oncology, The Johns Hopkins Hospital; Instructor, Department of Surgery, The Johns Hopkins School of Medicine
Matthew Hueman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology
Disclosure: Nothing to disclose.

Medical Editor

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 College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

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