Recent Advances in Cell Biology, Diagnosis and Therapy of ...

[Cancer Biology & Therapy 3:3, 251-258, March 2004]; ©2004 Landes Bioscience

Recent Advances in Cell Biology, Diagnosis and Therapy of Gastrointestinal Stromal Tumor (GIST) Review

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ABSTRACT

The understanding of mesenchymal neoplasms of the gastrointestinal tract has evolved dramatically over the last two decades since gastrointestinal stromal tumor (GIST) was described as the most common stromal tumor arising anywhere from the esophagus to the ano-rectum. Although morphologically similar to other benign and malignant smooth muscle and neural stromal neoplasms, GIST constitutes a distinct group of rare gastrointestinal tract tumors that originate from the interstitial cells of Cajal, regulators of gut peristalsis that normally express CD117, which is the product of the c-KIT proto-oncogene that encodes a tyrosine kinase receptor that regulates cellular proliferation in GISTs. Virtually all GISTs occur from mutations of the c-KIT oncogene and exhibit consistent expression of c-KIT (CD117), which is considered the most specific criterion for a diagnosis of GIST. Gastrointestinal stromal tumors vary in their behavior and several features have to be considered to assess their malignant potential. The advent of sophisticated imaging techniques for the evaluation and sampling of stromal tumors of the gastrointestinal tract has resulted in improved detection of GISTs. The identification of a novel tumor-specific target in c-KIT resulted in the development of a tyrosine kinase-inhibitor (imatinib mesylate) that provides an encouraging option for treating GISTs. This article reviews recent advances in the understanding of the cell biology, diagnosis, and therapy of GISTS.

Previously published onlnine as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cbt/abstract.php?id=615

KEY WORDS gastrointestinal stromal tumor, GIST, gastrointestinal tract, cell biology, diagnosis, therapy, imatinib mesylate

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ABBREVIATIONS

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Received 09/18/03; Accepted 12/10/03

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*Correspondence to: Roberto Logroño; The University of Texas Medical Branch; 9.300 J.S.A., 301 University Boulevard; Galveston, Texas 77555-0548; Tel.: 409.772.8438; Fax: 409.772.8437; Email: [email protected]

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Departments of Pathology1 and Medicine, Divisions of Medical Oncology2 and Gastroenterology3, The University of Texas Medical Branch, Galveston, Texas USA

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Roberto Logroño1 Dennie V. Jones2 Sohaib Faruqi3 Manoop S. Bhutani3

gastrointestinal stromal tumor proto-oncogene encoding a tyrosine-kinase receptor that regulates cell proliferation in GISTs immunochemical stain specific to c-KIT endoscopic ultrasonography fine needle aspiration cytology tyrosine-kinase inhibitor used as tumor-specific therapy for GISTs

INTRODUCTION

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GIST

Gastrointestinal stromal tumor (GIST) is a rare stromal neoplasm that arises from the muscularis mucosa or muscularis propria layers1 and represents the most common mesenchymal tumor of the gastrointestinal tract,2,3 accounting for 5% of all sarcomas.4 It has been estimated that anywhere from 2,500 to 5,000 cases may occur in the United States annually, though firm numbers are unknown5 as many of the studies published prior to 2000 most likely included other nonGIST entities such as leiomyosarcoma. The median age at presentation is around 60 years of age, with equal frequency in males and females. Most GISTs are sporadic and in 95% of the cases the lesion is solitary. A familial form consisting of multiple GISTs, systemic mast cell neoplasia, urticaria pigmentosa, hyperpigmentation of the mucous membranes and skin, and spindle cell hyperplasia within the myenteric plexus of the gut has been described.6-8 This syndrome is thought to be associated with a germ line mutation in the c-KIT gene. Gastric GISTs, along with pulmonary chondromata and extra-adrenal paragangliomata, comprise the rare Carney’s triad; no cause is known for this syndrome, which appears to have a predilection for young women.9,10 The vast majority of GISTs (up to 70%) arise in the stomach, with 20–30% originating in the small intestine and the remainder 10% occurring in the esophagus, colon, and rectum.11,12 Unlike epithelial tumors of the gut, most GISTs exhibit an endophytic growth pattern, growing within the bowel wall parallel to the gut lumen. The overlying mucosa may be preserved, especially in smaller or more indolent lesions, but larger and more aggressive tumors can display ulceration of the overlying mucosa. In up to one-third of patients the tumor invades an adjacent organ. Most GISTs are found incidentally during barium studies, endoscopy, or abdominal scans obtained for other reasons.11 The clinical presentation of these neoplasms is variable and depends on tumor size and anatomic site. Because of their submucosal location GISTs often produce local obstructive symptoms, particularly when arising in the esophagus or small intestine. Bleeding and ulceration can also rarely occur. Most GISTs usually present with vague upper abdominal pain, fullness, or bleeding; if severe enough, secondary symptoms and findings of anemia may also be noted. A palpable abdominal mass may or may not be present. GISTs can also

CD117

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EUS FNA Imatinib mesylate

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c-KIT

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ADVANCES IN CELL BIOLOGY, DIAGNOSIS AND THERAPY OF GIST

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neoplasms.11,22,25 A recent study by Miettinen and colleagues defined GIST as CD117-positive primary spindle or epithelioid mesenchymal tumors arising in the gastrointestinal tract, omentum, or mesentery.5 It is noteworthy that other neoplasms, such as malignant melanoma, small cell carcinoma of the lung, and malignant vascular tumors such as angiosarcoma and Kaposi sarcoma, can also express CD117. When the latter tumors occur in the gastrointestinal tract their differentiation from GIST can be challenging.5,26-28 Other studies have reported the occurrence of a subset of CD117negative GISTs.1 CD34 is a hematopoietic stem cell marker of unknown function whose expression in GISTs appears to correlate with the primary location of the tumor with positive staining ranging from 47% in small intestine to 100% in rectum and esophagus.1,2,11,29 A study by Wang and associates reported lack of CD34 expression in all benign GISTs and concluded that GISTs originate from CD34-positive stem cells, which differentiate to express the ICC phenotype. Furthermore, these authors suggested that CD34-negativity in benign GISTs probably indicates that these neoplasms are composed of more mature ICCs, as opposed to GISTs with malignant behavior composed of dedifferentiated ICCs expressing the stem cell marker CD34.30 Another study by Vanderwinden and coworkers reported the finding of CD34 expression on fibroblasts situated immediately adjacent to ICCs in the human intestine.31 As noted above, one of the distinguishing features of GISTs is the expression of c-KIT. The c-KIT gene is located in chromosome 4 (4q11-12) near the platelet-derived growth factor receptor and the gene for epidermal growth factor.23,30 The c-KIT gene is additionally expressed on hematopoietic stem cells, mast cells, melanocytes, basal cells of the skin, breast epithelium, and germ cells,30 and the occurrence of mutations in the c-KIT gene has been reported not only in GIST, but also in neoplasms affecting these cell lineages,6,26 as well as in small cell lung cancer and other lesions. C-KIT is the homologue of the Hardy-Zuckerman feline sarcoma virus and is the receptor for stem cell factor, also known as Steel Factor, mast cell growth factor, or KIT ligand. As a trans membrane tyrosine kinase, upon binding stem cell factor to the extra cellular domain c-KIT undergoes homodimerization and autophosphorylation. This activation step subsequently allows c-KIT to phosphorylate tyrosine residues on other proteins thus initiating intracellular signaling pathways, which lead to cellular proliferation and differentiation. Other tyrosine kinases which may be activated in neoplasia, such as the epidermal growth factor receptor and HER2/neu protein, are also associated with angiogenesis and protection against the apoptotic activity of chemotherapy and radiation therapy, and it has been suggested that the aberrant expression of c-KIT confers these additional qualities to the cells of GIST.32 Virtually all GISTs have activation of c-KIT usually due to mutations. Unlike native c-KIT, mutated c-KIT may not require the presence of stem cell factor for activation. Nearly all of the activating c-KIT mutations are due to in-frame mutations, which preserve the expression of the c-KIT protein. It appears that a c-KIT mutation is an early event in the genesis of a GIST lesion and mutations have been found at equal frequency among low-risk, high-risk, and metastatic GIST lesions.33,34 Some evidence suggests that the location of the mutation may be correlated with the biologic behavior of the tumor. The c-KIT gene has 21 exons and the majority of mutations have been found in exon 11, the intracellular juxtamembrane region, which modulates c-KIT activity through interactions with protein

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cause bowel obstruction and/or perforation, dysphagia (especially in the esophagus), fever, and obstructive jaundice, if near the ampulla of Vater. GISTs are tumors that display a highly peculiar specificity for their anatomic site of origin with several histological subtypes described in relationship to their occurrence in different segments of the gastrointestinal tract.13 The clinical behavior of GISTs varies from benign to malignant with the latter comprising approximately 10–30%.11 However, some authors consider GISTs as unpredictable tumors, which at least have low malignant potential,12 and have proposed a classification into low-risk and high-risk GISTs in order to better assess their potential for recurrence and metastasis.14 Other series reported that anywhere from 15% to 50% of patients may present with obvious metastatic disease15,16 and the majority (three-quarters) of patients who undergo complete resection of the tumor eventually developed metastatic disease. However, unlike other soft tissue sarcomas most metastatic GISTs are confined to the abdomen—liver and peritoneum—instead of the lungs. Isolated extra-abdominal metastases are rare enough to lead one to question the validity of the diagnosis; even when presenting with massive abdominal disease, extra-abdominal metastases are uncommon.17

CELL BIOLOGY

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Earlier studies on gastric stromal neoplasms, then generically known as “cellular leiomyomas”, indicated that the morphogenesis of these tumors was unclear and suggested a possible origin in multipotential gastric stromal stem cells capable of differentiating into smooth muscle.18 The term GIST was first offered in 1983 by Mazur and Clark and comprises most gastrointestinal tract tumors previously designated as leiomyoma, leiomyoblastoma, and leiomyosarcoma.11,19 Other mesenchymal neoplasms arising in the gastrointestinal wall include neural tumors such as Schwannoma and malignant Schwannoma. True GISTs lack the ultrastructural and immunohistochemical features of most other soft tissue sarcomas, smooth muscle and Schwann cells, and gut epithelial cells and tumors. Based on their cell of origin GISTs constitute a distinct group of gastrointestinal tract neoplasms originating from the intestinal pacemaker cells, the interstitial cells of Cajal (ICC), which are located in the myenteric plexus where their function is to regulate gut peristalsis; therefore, their designation as ‘pacemaker cells’.20-22 In the normal gut the interstitial cell of Cajal is known to express vimentin, CD34, and CD117. The latter immunostain is the product of the c-KIT proto-oncogene21-23 that encodes a tyrosine kinase receptor, which is responsible for cellular proliferation in GISTs.24 Maturation of the ICC is dependent on the interaction of serum stem cell factor and the c-KIT tyrosine kinase. Consistent expression of CD117 is characteristically exhibited by practically all variants of GIST regardless of their anatomic site or clinical behavior.11 Immunohistochemical expression of CD117 is considered the most specific diagnostic criterion for GIST.20-22 The interstitial cells of Cajal have proven to be the only cells in the gut that are immunoreactive with vimentin, CD34, and CD117 (c-KIT). Gastrointestinal stromal tumors express an identical immunophenotype, which indicates a likely origin from ICCs or possible differentiation along this line.21 Expression of c-KIT (CD117) by tumor cells occurs in an overwhelming majority of GISTs and constitutes the most important defining feature of these

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Figure 1. Stomach, excisional biopsy: GIST with spindle morphology, occasional perinuclear vacuoles, and presence of mitoses (arrow). H&E stain. X400

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by counting mitoses (Fig. 1) in 50 adjacent high-power fields (HPF)(with X40 objective and X10 ocular lenses);37,38 the mitotic count can also be determined on 10 HPF. In a large study on gastrointestinal smooth muscle tumors, Cunningham and colleagues reported an unfavorable prognosis for tumors having 10 or more mitotic figures per 50 HPF.37 Other authors have considered mitotic counts on GISTs as an indicator of malignancy in relationship with the anatomic site of origin of the tumor using a lower limit of five or more mitoses per 50 HPF for primary esophageal lesions,41 gastric,12 small intestine,42,43 colon,44 and anorectum.45,46 Other authors postulated that the separation of survival categories is maximal when a threshold of ten mitoses per 50 HPF is used.37,38 Similarly, it is generally agreed that when the mitotic index is determined on the basis of 10 HPF, GISTs with rates of ten or more mitoses are considered high-grade,11 while others consider rates of two or more mitoses per 10 HPF as indicative of high-risk and mitotic counts lower than two in 10 HPF as low risk GIST.14,22 Also, GISTs with mitotic rates of one or less per 10 or 50 HPF are often regarded as “benign”. Previous studies have proposed a stratification of risk potential on the basis of mitotic index into ‘benign’, ‘borderline’, and ‘malignant’ GISTS.29 However, the fact that even small tumors with no observed mitosis have later proven to behave in a malignant fashion38 indicates that all GISTs might be potentially malignant neoplasms and should better be regarded as low-risk or high-risk.14 Metastasis or invasion to adjacent organs, as established clinically or by imaging techniques, constitutes obvious evidence of malignant behavior in GISTs. Presence of tumor necrosis is highly suggestive of malignancy. Also, spindle morphology is associated with more aggressive behavior than epithelioid features in GISTs. Such GISTs with epithelioid cells were previously referred to as “leiomyoblastomas”.11 Recent advances in the prognostic assessment of GISTs include DNA ploidy, determination of the proliferative index by using the MIB-1 proliferation marker, and the application of cytogenetic studies to identify c-KIT mutations. Presence of aneuploidy was found to have statistically significant prognostic value in GISTs37 and when used in combination with image analysis the MIB-1 proliferative index proved highly predictive in the determination of the malignant potential of GISTs. One study reported high proliferative indexes on GISTs, which correlated positively with large tumor size, high mitotic counts, and tumor necrosis.47 The identification of mutations in the c-KIT gene was reported to have unfavorable prognosis by some studies,35,36 while opposite findings have also been reported.33 Despite some encouraging preliminary results none of these novel techniques is an accurate prognosticator of GISTs and much remains to be done in the determination of prognosis of such tumors.

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phosphatases and adapter proteins. GISTs with exon 11 mutations are thought to be associated with more aggressive lesions having decreased survival.35,36 However, in a separate study Rubin and coworkers observed the abundance of exon 11 mutations, but also mutations in the extracellular region and within two different areas of the tyrosine kinase regions; four of the 48 patients studied had no discernible c-KIT mutation.33 These investigators were unable to correlate the location of the mutation with the clinical outcome. Other mutations and loss of heterozygosity have also been reported with GISTs, but are thought to be secondary to tumor progression.

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TUMOR CRITERIA OF PROGNOSTIC SIGNIFICANCE

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A number of features of GIST tumors are known to have prognostic significance, thus assisting in the assessment of possible malignant behavior of GISTs. Among these criteria are patient’s age, anatomic location, tumor size, mitoses count, infiltration to adjacent organs, proliferation index, DNA ploidy, and cytogenetics. Imaging studies usually provide accurate information regarding the location of the mass and tumor size. The latter two criteria, along with mitotic count, are considered independent prognostic factors for this neoplasms.37,38 In a retrospective study of 1,004 cases at the Armed Forces Institute of Pathology, Emory and collaborators demonstrated that GISTs arising at different sites vary in their clinical behavior. In this study, esophageal and gastric GISTs had better prognosis than those arising in the intestines or rectum. Furthermore, these investigators noted that tumor size less than 5 cm was generally associated with favorable prognosis.14,37,38 Other studies have used 4 cm as a cutoff value for predicting the behavior of GISTs.1,39 Tumor size can be accurately assessed by endoscopic ultrasound (EUS), as well as presence of ulceration, necrosis, and cystic changes within a GIST, which are also considered as prognostic factors for malignancy.1,39,40 Mitotic count is a very important prognostic variable in the evaluation of GISTs. Different studies vary significantly in their assessment of tumor mitotic activity, which has lead to nonconcordant grading systems based on counting presence of mitoses per 10 or 50 high-power fields. The mitotic index is calculated on tissue sections


DIAGNOSTIC APPROACHES Histopathologic and Immunohistochemical Examination. On tissue sections GIST often presents with moderate to high cellularity and tumor cells vary from spindle (70–80%) to epithelioid (20–30%). The latter variant corresponds to the former designation of leiomyoblastoma. Prominent nuclear pleomorphism is uncommon in GISTs.11 Spindle-cell GISTs often exhibit numerous spindle cells with occasional palisading and perinuclear vacuoles (Fig. 1). Malignant spindle gastric GISTs tend to lose these vacuoles. Epithelioid GISTs are composed of more rounded epithelioid cells, which may show pleomorphism and/or mitoses, but typically have a more benign clinical course than their spindle counterparts.12


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Figure 3. Stomach, computed tomography-guided core biopsy: GIST with strong expression of CD34 immunostain. X400

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Figure 2. Stomach, excisional biopsy: GIST with diffuse expression of CD117 immunostain. X400

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The histopathologic diagnosis of GIST requires confirmation with immunostain for CD117, which is expressed by practically all GISTs with a diffuse or membranous staining pattern (Fig. 2).12 Expression of CD117 is observed in both spindle and epithelioid GISTs.22 It is important to keep in mind that, as noted above, other malignant neoplasms can also express CD117, such as: malignant melanoma, seminoma, sarcomas, and certain types of leukemia.22 Approximately 70–80% of GISTs also express CD34 (Fig. 3).21,29 A recent study on GISTs suggested that CD34 positivity was a good indicator of malignant phenotype.30 However, other studies have provided preliminary data indicating that loss of CD34 or CD117 immunoreactivity might be indicative of malignant behavior in GISTs.21-22 Additionally, GISTs can also express smooth muscle actin in approximately 30% of cases, but are often nonreactive with desmin and S-100 protein immunostains.22 Endoscopic Ultrasound. Endoscopic ultrasound (EUS) is a high resolution imaging modality that has emerged as the most useful technique for further characterization of submucosal lesions involving the gastrointestinal tract. Imaging by EUS provides a characteristic five-layer echo pattern that correlates with histology (1st layer-superficial mucosa, 2nd layer deep mucosa, 3rd layer-submucosa, 4th layer muscularis propria and 5th layer serosa or adventitia) in the esophagus and rectum. Using linear array EUS instruments that allow visualization of a needle under real-time ultrasound imaging, trans-gastrointestinal EUS- guided fine needle aspiration (FNA) can be performed on a variety of lesions including the pancreas, lymph nodes and submucosal gastrointestinal tumors.48 Gastrointestinal stromal tumors on EUS appear as hypoechoic masses involving the 3rd or the 4th echo layer corresponding with the submucosal layer and the muscularis propria (Fig. 4). CD-117 negative tumors such as true leiomyomas or leiomyosarcomas have similar EUS features as GISTs and, thus, EUS imaging alone is unable to differentiate such tumors from GISTs. However, EUS imaging does provide important morphological information regarding submucosal lesions (GIST and nonGIST), including some features suggestive of malignancy: size greater than 3–4 cm, irregular margins, internal echogenic foci or cystic spaces, adjacent lymph nodes, and rapid growth rate at follow-up EUS.1,39,49,50 Establishing a final

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Figure 4. EUS image of a hypoechoic, 3 by 3 cm submucosal mass in the stomach consistent with a diagnosis of GIST.

pathologic diagnosis requires tissue sampling for microscopic examination. Endoscopic ultrasound-guided FNA is a recently developed technique that permits real-time ultrasonic-guided aspiration of intramural or extramural lesions, which enables the endoscopist to obtain samples for diagnostic cytology. The impact of this technology on clinical-decision making is quickly evolving. Initial experience with EUS-FNA on submucosal lesions resulted in accurate diagnosis obtained in only around 60% of the patients.51,52 However, by adding immunohistochemical analysis to the microscopic evaluation, recent data has shown that the accuracy rate of EUS-FNA for submucosal diagnosis may potentially increase to levels above 90%.40 In a recent study1 of 40 patients with submucosal gastrointestinal tumors the authors were able to show that expression of CD-117




Figure 5. Stomach, EUS-FNA: GIST. Notice spindle nuclei with tapered ends in parallel arrays. Papanicolaou stain X400

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immunostain in EUS guided FNA material correlated with a greater chance of malignant features in surgical resection specimens, including increased number of mitoses per high power field, when compared to EUS-FNAs that were negative for CD-117. When EUS-FNA is performed having an on-site pathologist for assessing specimen adequacy the chances of obtaining an adequate sample for cytological evaluation are higher.53,54 Furthermore, by having on-site pathological examination of the specimen, pathologists can often provide a preliminary diagnosis on the basis of which additional aspirates can be requested to perform ancillary studies and special immunohistochemical stains, as required.53 This approach provides an ideal scenario for sampling submucosal gastrointestinal tract tumors via EUS-FNA since confirmatory special immunostains for CD117 and CD34 is required for diagnosing GIST. Additionally, establishing a confirmed pathologic diagnosis of GIST in a preoperative setting permits the planning of further therapy in a more thorough manner than if a pathological diagnosis was not available at the time of surgery. Fine needle aspiration guided by computed tomography55 or by ultrasound55,56 may also be used for the cytological diagnosis of mesenchymal tumors arising in the gastrointestinal tract wall. Limitations of preoperative image-guided FNA may be due to inadequate sampling of the target mass lesion. Sample size is sometimes insufficient for performing ancillary studies or even for a routine cytological evaluation.1 In such cases performing confirmatory immunostains is not always possible and a conclusive diagnosis of GIST cannot be rendered on the basis of aspiration cytology. Other times the aspirates may be obscured by significant amounts of blood, which impairs the recognition of diagnostic cells. Technical pitfalls refer to the production of suboptimal slide preparations at the time of specimen collection such as significant air-drying artifact on alcoholfixed smears, which precludes adequate microscopic examination of the specimen. Technical difficulties can be avoided by having the slide preparations performed at the endoscopy suite by cytology technicians or, alternatively, by gastrointestinal endoscopy personnel previously trained in preparing adequate cytology materials.53 Another limitation of assessing GISTs via aspiration cytology is that performing mitotic counts is often difficult on aspiration cytology smears40,57,58 even if these were adequately cellular. Furthermore,

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due to sampling bias mitotic counts on cytology material might not be representative of the entire neoplastic mass. The FNA cytology appearance of GIST has been previously described.3,25,57-61 Aspirates usually consist of monotonous spindle neoplastic cells having cigar-shaped, tapered-end nuclei, which arrange in fascicles with parallel arrangement of nuclei and occasional nuclear palisading (Fig. 5). The cytoplasm of neoplastic cell varies from scant to moderate and delicate, and the cell membranes are often inconspicuous, thus conferring a syncytial appearance to the tumor.57 Tumor cell fragments are often seen in association with capillary vessels. Occasional nuclear pleomorphism can be identified, as well as presence of epithelioid neoplastic cells25,59,61-63 and numerous single cells with stripped nuclei.3 It has been postulated57 that most cases of gastric smooth muscle tumors reported in earlier studies55 might indeed represent GISTs, as indicated by the fact that immunostains for CD117 or CD34—required for the diagnosis of GIST- were not carried out on these gastric tumors, in addition to the fact that GIST is a much more common gastrointestinal mesenchymal neoplasm than leiomyoma and leiomyosarcoma. It is now known that most GISTs with spindle-cell morphology correspond to tumors previously diagnosed as leiomyoma or leiomyosarcoma, whereas epithelioid GISTs were previously referred to as leiomyoblastoma.63 Some authors recommend the use of an immunohistochemical panel comprised of CD117, CD34, and desmin in the cytological diagnostic assessment of gastrointestinal tract tumors suspected of being GIST.61 Obtaining a cytopathological diagnosis of GIST preoperatively by percutaneous image-guided FNA or by EUS-FNA allow a more precise planning of surgery and, even in nonsurgical patients, appropriate prognostic information can be obtained and therapy can be applied.


DIFFERENTIAL DIAGNOSIS The differential diagnosis of mesenchymal tumors arising in the gastrointestinal tract wall includes smooth muscle and neural neoplasms. Smooth muscle and Schwann- cell tumors often present with spindle-cell morphology, as is usually the case with GISTs. The occurrence of leiomyoma, leiomyosarcoma, Schwannoma, and malignant Schwannoma in the gastrointestinal tract is extremely rare,13 whereas GIST constitutes the most common mesenchymal neoplasm of the gastrointestinal tract.3 Epithelioid GISTs have to be differentiated from adenocarcinomas.63 The appropriate utilization of immunohistochemical stains is essential in determining the true nature of mesenchymal neoplasms of the gastrointestinal tract. Expression of CD-117 is a distinctive attribute of GISTs as compared with smooth muscle and neural tumors, which are negative for this marker. Similarly, CD34 is often expressed in GISTs, but absent in nonGIST mesenchymal tumors of the gastrointestinal tract. Smooth muscle differentiation is typical of leiomyomas and leiomyosarcomas, which usually express desmin and smooth muscle actin. Lack of reactivity with desmin is typical of GISTs, although some GISTs can express actin. Expression of neural markers such as S-100 protein is typical of both benign and malignant Schwannomas, but is usually absent in GISTs.

TREATMENT OPTIONS As with most gut tumors the only realistic chance for cure with GIST remains definitive surgery. In cases where adjacent structures are involved, an en-bloc resection with a rim of normal tissue should


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patients).76 On the basis of these trials, as well as additional evidence of clinical activity, the US Food and Drug Administration approved imatinib mesylate for use in CD117-positive unresectable GIST in February 2002. Nearly 90% of GIST patients treated with imatinib mesylate experience significant symptom relief. Evidence of biologic activity can be observed within a few hours after the initiation of therapy, as demonstrated by a decrease in 18fluorodeoxyglucose uptake by positron emission tomography, an effect that mimics the in-vitro decrease in glucose uptake after exposure to imatinib.77 The median time to objective response is approximately three months. Hepatic GIST lesions may never fully resolve, but may acquire a cyst-like appearance on computed tomography. Histologically, these lesions are essentially hyaline deposits, though CD117-positive cells of uncertain malignant potential may remain around the periphery of the lesion. One study suggests that the ability to achieve a response to imatinib may be related to the presence and location of the c-KIT mutation; patients with exon-11 mutations had a 72% response rate, compared to a 32% response rate for exon 9 mutations and a 12% response rate for those with no detectable mutation.78 These findings remain to be confirmed by other studies on a larger patient population. While the application of imatinib has revolutionized the therapy of GIST much work remains to be done. It is unclear how long the responses will last or if they require maintenance therapy. Furthermore, while clinical benefit is seen in a majority of patients few of the responses are complete. As many of the patients with completely resected GIST eventually relapse, could there be a role for imatinib in adjuvant therapy? And finally, as a greater understanding of the molecular biology of GIST and other neoplasms is better delineated, imatinib-based combination regimens utilizing additional targeted therapies are sure to be investigated.

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be attempted if possible.64 Since a true tumor capsule does not exist the surgeon must exercise additional care during the removal of a GIST not to rupture the tumor, as this complication is associated with an increased risk for the development of peritoneal metastases.65 In common with most other soft tissue sarcomas GISTs do not usually metastasize to regional lymph nodes, thus a regional lymphadenectomy is not necessary.64,66 An aggressive surgical approach is warranted for GISTs as patients undergoing complete tumor resection have a superior outcome compared to those who have undergone only a partial resection.15,65,67 DeMatteo and associates noted a trebling of the median survival (66 versus 22 months) after complete resection as opposed to an incomplete resection of GIST.4 Retrospective data demonstrates a five-year overall survival for more than half of the patients who underwent a complete resection of their GIST, as opposed to a median survival of only 9–12 months for an incomplete resection.68 Data also suggests a potential benefit of radical surgery in a selected subgroup of patients with advanced disease, such as patients with a solitary metastasis that develops after a prolonged disease-free interval, especially with moderately to well-differentiated histology, which may have a better overall outcome.69,70 In patients with unresectable GIST surgery is best suited for palliation of localized problems such as bleeding, perforation, or obstruction. Radiation therapy is usually reserved for palliation of symptoms as well. However, both in-field and out-of-field recurrences are common.15 Until recently, drug therapy for patients with GIST has been ineffective. In a trial by Edmonson and associates,71 patients with GISTs were administered a regimen of dacarbazine, mitomycin C, doxorubicin, cisplatin and granulocyte-macrophage colony stimulating factor. Only one response out of 21 was observed (4.8%), though the median survival was 16.7 months.71 In an additional trial of doxorubicin and dacarbazine, only 3 of the 43 patients with gastrointestinal soft tissue sarcomas, including GISTs, responded to the therapy.72 A regimen of etoposide and ifosfamide produced no responses among patients with GIST or other gastrointestinal sarcomas.73 Anecdotal reports of hepatic arterial embolization, with or without chemotherapy, have also been published, but there is insufficient data to suggest any clear clinical benefit. The identification of the c-KIT oncogene and the development of imatinib mesylate (Gleevec, Novartis), which is an inhibitor of the type III tyrosine kinases such as c-KIT, provided a paradigm shift in the treatment of GISTs with potential implications for other solid tumors. Imatinib mesylate was initially evaluated for its ability to inhibit the BCR-ABL hybrid tyrosine kinase of chronic myelogenous leukemia. It also inhibits the tyrosine kinase activity of c-ABL, c-KIT and the platelet-derived growth factor receptor by competing with ATP in the tyrosine-binding site. It is a small molecule that is orally bio-available, very well tolerated, and can be dosed once daily. Data from chronic myelogenous leukemia studies indicate that 400 mg per day is the minimally effective dose, and it appears that this dose is sufficient for GIST therapy.74,75 Two trials of imatinib in GIST have been reported thus far. The larger of the two, the US-Finland Study,75 evaluated 147 patients with unresectable GIST treated at either 400 mg/day or 600 mg/day and reported an objective response rate of 54%, and an additional 28% had a minor response or stable disease.75 The second study, sponsored by the European Organization for Research and Treatment of Cancer, evaluated 36 patients receiving dose of 400 mg to 1000 mg per day and noted disease progression in only 11% (four

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