Gastric Stromal Tumors

Synonyms and related keywords: malignant gastric stromal tumors, gastric leiomyosarcomas, gastrointestinal stromal tumors, GISTs, gastric GIST, fibrosarcoma, angiosarcoma, hemangiopericytoma, gastric smooth muscle tumors, intestinal smooth muscle tumors


INTRODUCTION

Background: Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the gastrointestinal (GI) tract defined by the expression of c-KIT (CD117) in the tumor cells. Previously, these tumors were classified as gastric or intestinal smooth muscle tumors; however, this traditional classification was abandoned with the advent of immunohistochemical methods enabling the specific identification of c-KIT–positive tumors. GISTs are rare and constitute only 1% of all malignant tumors of the GI tract; nevertheless, they are the most common mesenchymal neoplasm of the GI tract. GISTs are found in the stomach in 47-60% of cases, yet they are the least prevalent malignant tumors of the stomach, constituting only 1-3% of all malignant gastric tumors. While GISTs can occur at any point along the GI tract, the focus of this article is on GISTs of the stomach.

Histologically, GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones. By definition, GISTs are CD117 positive, although positivity for nestin and CD34 is also common.

Characteristics of GISTs that are predictive of malignancy are mitotic rate greater than 5 per 10 high-power fields (HPFs) or size larger than 5 cm. However, tumors with low mitotic index can also metastasize, and gastric GISTs are commonly less aggressive than those of nongastric intestinal origin.

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 of time 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:

• In the US: An estimated 150 new cases are diagnosed each year, with an annual incidence of 0.07 cases per 100,000 population.

• Internationally: 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 histologic grade. In general, GISTs portend a much better prognosis than adenocarcinoma of the stomach.

Race: No racial predilection exists.

Sex: No gender 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 may include abdominal pain, anorexia, nausea, vomiting, weight loss, epigastric fullness, and early satiety.

• Occasionally, GISTs can be found incidentally. 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.

DIFFERENTIALS

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.

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

Lab 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. CT scanning can also be used to evaluate tumor invasion to adjacent structures and the presence of intra-abdominal metastasis. As mentioned, findings on CT scanning can often be confused with masses originating from adjacent structures.

• Endoscopic ultrasonography: Endoscopic ultrasonography (EUS) is a valuable tool in the diagnosis and preoperative assessment of gastric GISTs. It can demonstrate the submucosal location of the tumor and can define its size, borders, and echoic pattern. Ultrasonic features associated with increased risk of malignancy are large tumors, tumors with irregular extraluminal borders, and the presence of cystic spaces and echogenic foci. Diagnosis can often be made using ultrasonographic-guided biopsy. However, while the histology obtained may be able to demonstrate a spindle cell tumor, differentiating between benign and malignant forms is often difficult (see Histologic Findings).

Procedures:

• Upper endoscopy: This usually is the first examination performed in the evaluation of patients with upper gastrointestinal symptoms. Gastroscopy may demonstrate a firm, smooth, yellowish submucosal mass, which can be ulcerated. Nevertheless, these tumors can be missed because of their frequent submucosal and extraluminal growth.

• Preoperative biopsy: Preoperative biopsy is not always indicated. Surgical resection is required for treatment and for definitive diagnosis in most cases. Biopsy is important 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 often are 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. Consider this procedure 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. However, this histologic appearance is not uniform. A similar tumor with a predominant epithelioid component was historically diagnosed as leiomyoblastoma. This variant is occasionally associated with a well-defined condition called Carney syndrome.

Important histologic factors to consider in evaluating these tumors are mitotic index, cellularity, necrosis, nuclear atypia and nuclear-cytoplasmic ratio, cell shape, amount of stroma, and vascularity.

Investigations of GISTs by immunohistochemistry and electron microscopy (ultrastructural parameters) reveal phenotype variability that includes myoid, neural, and indeterminate characteristics. Study of GISTs by immunohistochemistry methods reveals expression of CD117 and other various antigens, such as nestin (90-100% positivity), CD34 (70% positivity), CD44, 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. Positive CD117 staining in a spindle-shaped cell GI tumor is diagnostic for GIST. 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.

Recent studies suggest that GISTs may originate from the interstitial cells of Cajal. These cells are distributed along the GI tract and play a role in the control of gut motility. The interstitial cells of Cajal exhibit both myeloid and neural features and express the c-kit proto-oncogene receptor. However, the fact that GISTs are detected (although very rarely) outside of the GI tract (ie, omentum, mesentry, retroperitoneum) argues against this hypothesis.

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.

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 HPFs 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 HPFs 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 HPFs.

• Tumor size

• T1- Tumor less than 5 cm, localized

• T2 - Tumor greater than or equal to 5 cm, 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: No standard regimen for adjuvant therapy presently exists for malignant gastric stromal tumors.

• Data regarding the use of radiotherapy in an adjuvant setting failed to show a statistically significant benefit.

• Current data suggest a major role for the tyrosine kinase inhibitor, imatinib mesylate (STI-571, Gleevec), for patients with GISTs. Numerous trials have demonstrated substantial tumor response in patients with metastatic or advanced disease.

• The Food and Drug Administration (FDA) approved imatinib mesylate for GIST on February 1, 2002, under accelerated approval regulations and under the orphan drug program, which provides financial incentives for drugs developed to treat rare diseases (ie, diseases that affect fewer than 200,000 patients). Imatinib had first been used in patients with chronic myeloid leukemia (CML), which is characterized by a balanced translocation between chromosomes 9 and 22 (the Philadelphia chromosome). This abnormality results in the production of the BCR-ABL fusion protein, which has uncontrolled tyrosine kinase activity. Imatinib has been found to induce a near-complete response in virtually all patients treated in the chronic phase of CML.

• 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.

• 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. 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. The main operative principle is resection of the tumor with clear margins, preferably about 2 cm wide.

• For small gastric tumors, wedge resection is adequate, if technically possible. 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 and has not been shown to yield any survival benefit.

• 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.

• 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.

MEDICATION

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

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

Drug Name	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.
Adult Dose	400 mg PO qd with food; may increase to 800 mg/d divided bid in absence of adverse effects
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
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
Pregnancy	D - Unsafe in pregnancy
Precautions	Dose must be reduced if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develop

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

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; concurrent administration with St John's wort
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)
Pregnancy	D - Unsafe in pregnancy
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 and histologic grade.

• 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 gastric stromal tumors range from 32-93%. In large series, this rate is about 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.

• 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:
  • 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 (see Table 2).

  Table 2. Five-Year Survival According to Size and Number of Mitoses

  Size cm	Mitoses per 20 HPFs	5-Year Survival Rate
  less than 6	less than 4	97.5%
  >6	less than 4	91.5%
  less than 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. The 5-year survival rate dropped to 32% in patients with high-grade tumors.

• 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

Medical/Legal Pitfalls:

• No consensus has been reached regarding a uniform staging system, and none of the currently used classifications is fully satisfactory.

• No standard regimen for adjuvant therapy presently exists for malignant gastric stromal tumors.

• Direct every effort at avoiding tumor rupture during surgical therapy. Tumor rupture is associated with a worse prognosis 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 is rare but is reported.