The Current Management of Gastrointestinal Stromal Tumors

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HAPTER 10

The Current Management of Gastrointestinal Stromal Tumors David T. Efron, MD Assistant Professor of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland

Keith D. Lillemoe, MD Jay L. Grosfeld Professor and Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana

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astrointestinal stromal tumors (GISTs) are uncommon abdominal malignancies. Despite being the most common GI sarcomas, GISTs represent only 1% of alimentary tract tumors. Although these tumors of mesenchymal origin have been recognized for decades, recent developments have led to a better understanding of their cell of origin and the molecular events in their development. This knowledge has made the GIST a malignancy of great interest, and treatment options targeting specific molecular events have been developed. The pathologic features, clinical presentation, and treatment of GISTs are reviewed, and the challenges and opportunities that these tumors offer in the current era are presented.

PATHOLOGY The term gastrointestinal stromal tumor is a relatively new moniker currently used to encompass tumors of mesenchymal origin arising in the alimentary tract that share a similar clinical and biological behavior. Traditionally, because features indicative of smooth muscle were identified by routine staining under light microscopy, these tumors were labeled as leiomyoma, leiomyosarcoma, and leiomyoblastoma (of which the latter 2 demonstrated malignant features). Advances in Surgery®, vol 39 Copyright 2005, Mosby, Inc. All rights reserved.

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Over the last decade, ultrastructural examination via electron microscopy and immunohistochemical staining has allowed identification of features in these tumors that resemble both smooth muscle and neural tissue, as well as highly undifferentiated cells.1 GISTs demonstrate a variety of gross morphological features in relation to the wall of the GI tract. Tumors can be endoluminal, intramural, or exophytic. The latter may remain integrally incorporated with the wall or have the only attachment be a stalk sprouting from the external surface of the bowel (Fig 1). The mass, when identified endoscopically, may be characterized by an unblemished overlying mucosa; as a result, an endoscopic biopsy often reveals normal mucosa. Alternatively, the mucosa may demonstrate ulceration (Fig 2). Stromal tumors are often fast-growing tumors that outstrip their

FIGURE 1. Gastric stromal tumor demonstrating small stalk connection to the stomach wall and the irregular shape of the lesion. The pseudocapsule is easily seen.

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FIGURE 2. Endoscopic visualization of a proximal gastric gastrointestinal stromal tumor. Note the extrinsic compression of the gastric wall by the mass as well as the fistulous ulceration at the center of the bulge.

blood supply, resulting in a necrotic center. This endoluminal ulceration frequently results in a fistulous connection to the tumor’s necrotic center. GISTs are grossly irregular and eccentric in shape and, although not surrounded by a true capsule, their edges are usually selfcontained and easily identified by a pseudocapsule (Fig 1). Occasionally, the tumor will grow into the surrounding tissue and will invade adjacent organs. Because they may outgrow the blood supply of their tissue of origin, GISTs can be saprophytic, scavenging their blood supply from omentum and other organs. Bulky adenopathy is not characteristically seen because GISTs rarely demonstrate lymphatic spreading. Consequently, extensive lymphadenectomy at the time of resection is not warranted. Under routine light microscopy with the use of hematoxylin and eosin staining, intestinal stromal tumors classically demonstrate epithelioid or spindle cell patterns or, to a lesser extent, a mixture of

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both. If this method is used alone, it is often impossible to identify the specific tissue origin of the malignancy. Some of the tumors will exhibit smooth muscle features while others will demonstrate neural characteristics. Electron microscopy has aided in the separation of these tumors from true smooth muscle tumors because of the lack of smooth muscle characteristics (actin filaments) at the ultrastructural level and the demonstration of features consistent with neural tissue.2-6 The advent of immunohistochemical staining and its application to pathologic diagnoses has also allowed more accurate identification of these tumors. Some of the more common immunohistochemical markers used historically in the differential diagnosis of GISTs are delineated in Table 1. Previously, these markers were used to identify tissue subtypes that could potentially give rise to the neoplasm; they are currently still in use. CD117 has become the predominant immunomarker for the identification of GISTs. Despite an increasing understanding of these tumors, the true cell of origin of GISTs remains unclear. Although it is unknown whether these tumors represent a dedifferentiation from neural elements such as Schwann cells, enteric glia (perineural cells), or smooth muscle cells, a more recent theory favors the interstitial cell of Cajal as the cell of origin for these neoplasms.7,8 The interstitial cell of Cajal has been identified as the GI pacemaker cell; it carries both neural and smooth muscle elements and is known under normal circumstances to express CD117, which smooth muscle cells and neural cells do not. Because of this, the interstitial cell of Cajal or a progenitor cell is favored as a likely source of these neoplasms.

TABLE 1. Common Immunohistochemical Markers for Differentiation of Gastrointestinal Stromal Tumors Marker

Tissue Type

S100 Desmin Actin Vimentin CD34 Ki-67 PCNA CD117

Peripheral and central neural tissue Skeletal, smooth, and cardiac muscle intermediate filament Alpha-smooth muscle actin is muscle specific Mesenchymal tissue, intermediate filaments Vascular/endothelial markers, especially neoplastic Cellular proliferation Cellular proliferation Mast cell lineage diseases, gastrointestinal stromal tumor, acute myeloid leukemia, Ewing’s sarcoma, lung cancer

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By far the most significant immunomarker for GISTs is CD117 (KIT). KIT is a growth factor receptor that, when activated, has tyrosine kinase activity. KIT is normally an inactive transmembrane protein but, when bound, activates a number of proteins, including MAP kinase, STAT5, RAS, JAK2 and PI3 kinase.9 These activated proteins contribute to the processes of cellular proliferation, adhesion, and differentiation.10 KIT expression occurs under the control of the c-KIT proto-oncogene, which has been localized to chromosome 4q11-q12. A number of mutations in the c-kit proto-oncogene have been identified and have been shown to lead to constitutive activation of the KIT receptor, thus providing a continual stimulus for proliferation. These so-called gain-of-function mutations may contribute to the biological behavior of GISTs and may be key to understanding the malignant transformation of the interstitial cells of Cajal.11 Many pathologists believe that KIT expression is pathonomonic of GISTs and may be a required component for the diagnosis.12 Several studies have suggested that a small percentage of stromal tumors will stain negative for CD117.13-15 This may be the result of false-negative staining, a tissue sampling error, or low-level expression. Overall, the pathologic diagnosis of GISTs should be achieved with a combination of characteristics. Clinical and biological information should be combined with characteristics observed on light microscopy and immunohistochemical analysis that includes KIT staining, and, if needed, electron microscopy.16 In addition, a small percentage of GISTs that are negative for the c-kit mutation demonstrate a mutation of another tyrosine kinase receptor, plateletderived growth factor receptor alpha. These tumors progress and behave similarly to those with KIT mutations.17,18 DEFINITION OF MALIGNANCY The most reliable indicator of malignancy for GISTs is the identification of metastasis or local invasion in the workup or at the time of the operation for resection of the tumor. Although a number of clinicopathologic features have been implicated in the determination of malignant potential, even those that demonstrate the best correlation only allow the prediction of relative risk. That is, all stromal tumors may potentially be malignant, and predicting their behavior remains difficult. The 2 strongest predictors of GISTs’ behavior remain tumor size and mitotic activity. Large tumors (>10 cm in greatest diameter) and

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Very low risk Low risk Intermediate risk High risk

Size*

Mitotic Count†

<2 cm 2-5 cm <5 cm 5-10 cm >5 cm >10 cm Any size

<5 per 50 HPF <5 per 50 HPF 6-10 per HPF <5 per 50 HPF >5 per HPF Any mitotic rate >10 per HPF

* Size represents the single largest dimension. This may vary somewhat before and after fixation and between observers. There is a general but poorly defined sense that perhaps the size threshold for aggressive behavior should be 1 to 2 cm less in the small bowel than elsewhere. †Mitotic count should be standardized according to the surface area examined (based on size of high-powered fields), but definitions have not been agreed on. Despite the inevitable subjectivity in the recognition of mitoses and the variability in the area of high-powered fields, such mitotic counts still prove useful. Abbreviation: HPF, High-powered fields. (Courtesy of Fletcher C, Berman J, Corless C, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Int J Surg Pathol 10:81-89, 2002, Used with permission.)

tumors with high mitotic activity (>10 mitoses per high-powered field) reliably demonstrate malignant behavior and, thus, are classified as high risk. Conversely, small tumors (<2 cm) with a paucity of mitoses (<5 per high-powered field) are believed to be low risk. Because the risk of malignant behavior remains for all tumors, the absolute classifications of benign and malignant have been avoided in favor of a prediction of relative risk, given the clinicopathologic profile of the lesion. At a 2001 consensus conference on GISTs, a proposed delineation of the risk of tumor behavior was outlined (Table 2).12 Size is an independent predictor of the prognosis, but small size alone is insufficient to assure low risk; similarly, patients with GISTs with low proliferative activity are not assured of a benign course.19 Although it is possible that these tumors may undergo malignant transformation, it is more likely that malignant GISTs grow faster and achieve larger sizes by the time of diagnosis. Although a number of other features such as the cellular proliferation marker PNCA,20-22 DNA ploidy, flow cytometric analysis,23-26 telomerase activity,27 tumor suppressor gene hypermethylation,28 and tumor necrosis29 have been implicated as prognostic predictors, only size and mitotic activity have been consistently found to be predictive.

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INCIDENCE AND DISTRIBUTION Approximately 4500 to 6000 cases of GISTs are diagnosed annually in the United States. They can arise in patients of any age; however, the peak incidence appears to be between the sixth and seventh decades of life, and they are found fairly equally in men and women. In addition, there is an association of GISTs and neurofibromatosis.30 The stomach is the most frequent organ of origin for GISTs, but they may arise in all segments of the alimentary tract (Fig 3). In most series, gastric tumors are found in 45% to 65% of patients, followed by tumors of the small bowel (15%-25%), colon–rectum (5%-10%), esophagus (5%-10%), and duodenum (3%-5%).

CLINICAL PRESENTATION GI bleeding is the most common presenting symptom for GISTs at any organ of origin. Bleeding most frequently occurs because fastgrowing tumors outgrow their blood supply, create central necrosis, and develop a fistulous erosion into the GI tract. Bleeding is often slow, self-limited, and tends to be seen with anemia rather than with evidence of hypotension. In some cases, rupture of the tumor can

FIGURE 3. Cartoon graphic demonstrating the distribution of 173 primary gastrointestinal stromal tumors diagnosed and treated with surgical excision between 1968 and 2001 at the Johns Hopkins Hospital. (Courtesy of Efron DT, Lillemoe KD, Cameron JL, et al: Surgical management of gastrointestinal stromal tumors: A single institution 33-year experience. Gastroenterology 120:A41, 2001. Used with permission from the American Gastroenterological Association.)

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TABLE 3. Common and Site-Specific Presentation: Percentage of Tumors With Presenting Signs by Site (123 Symptomatic Gastrointestinal Stromal Tumors)

Site Esophageal Gastric Duodenal Jejunoileal Colorectal TOTALS

Gastrointestinal bleeding

Abdominal pain

Abdominal mass

Weight loss

17 39 38 20 36 34

— 22 13 45 — 23

— 27 13 15 — 20

— 6 13 — — 5

Site-Specific Symptoms Dysphagia 50% — Jaundice 6% Obstruction 15% Rectal Mass 27%

(Courtesy of Efron DT, Lillemoe KD, Cameron JL, et al: Surgical management of gastrointestinal stromal tumors: A single institution 33-year experience. Gastroenterology 120:41A, 2001. Used with permission.)

occur into the free peritoneal cavity and will occur with abdominal pain and hypotension consistent with massive intra-abdominal bleeding. Nonspecific abdominal pain or discomfort and obstructive symptoms are also common on presentation (Table 3). Because these tumors arise from all parts of the GI tract, the presenting symptoms may be quite varied. Obstructive symptoms are usually site specific; furthermore, dysphagia is common for esophageal tumors, and nausea, vomiting, and early satiety are frequently seen in association with gastric stromal tumors. Obstructive jaundice is seen with periampullary tumors, and clinical symptoms of bowel obstruction are seen with tumors arising from the alimentary tract distal to the ligament of Treitz. Up to 20% of GISTs may be seen as asymptomatic abdominal masses. In many cases, because of their eccentric location, tumors can reach a large size without causing specific symptoms. Finally, in some patients, the tumor is detected at the time of abdominal imaging for other indications or at laparotomy as an incidental finding for another condition.31

DIAGNOSTIC EVALUATION AND STAGING The nonspecific symptoms associated with GISTs lead to a wide variety of investigational studies and diagnostic options that are usually tailored to the suspected pathologic site. GI contrast studies may include a barium swallow test, small bowel follow through, enteroclysis, or a barium enema. In many cases, these studies may have normal results or show only subtle changes, especially if the tumor is eccentric in location and, therefore, does not alter the GI mucosal

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pattern. External compression may be seen with a tumor of significant size. Similarly, upper or lower endoscopy performed for GI blood loss may show a normal mucosal pattern with the exception of a small ulcer representing the communication site with the large necrotic tumor mass. Endoscopic ultrasound may be useful in defining the mass and its relationship within the layers of the bowel wall.32-34 Computed tomography (CT) is the single most useful diagnostic test because it gives information about the tumor size, anatomical location, and evidence of tumor necrosis or metastasis.35-37 In cases of large tumors, the mass may be of such size that the actual organ of origin cannot be determined. This is particularly true of large gastric GISTs, which may appear to be a primary tumor arising from the liver, pancreas, stomach, spleen, or colon (Fig 4). Magnetic resonance imaging can provide similar information to CT scanning

FIGURE 4. Computed tomographic scans (A and B) and magnetic resonance imaging (C) demonstrating the necrotic, liquefying center of various gastric stromal tumors. Radiographically, it is often difficult to distinguish the true organ of origin and whether invasion of adjacent structures has occurred.

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FIGURE 5. Computed tomographic and positron emission tomographic scans of a patient with a recurrent jejunal gastrointestinal stromal tumor detected 13 months after complete resection. The recurrence was noted in the right upper quadrant (white arrow). Side by side comparison of (A) before and (B) after imatinib therapy (400 mg/d) demonstrates regression of gross mass and no residual metabolic activity.

but offers no specific information and is seldom indicated as an additional procedure. Recently, positron emission tomography (PET) has been shown to be potentially useful in the diagnosis and management of GISTs. CT scans can identify necrotic characteristics of the tumor, but the morphological findings of these tumors under treatment with tyrosine kinase inhibition may lag by several months after initiation of therapy. Fluorodeoxyglucose-PET is able to identify the metabolic activity of cells within a residual tumor mass and may provide earlier insight about the tumor response. In one study, Antoch et al38 showed that the combination of CT scans and PET scans identified more lesions than did either CT or PET alone. Furthermore, when used in side-by-side evaluation, even more lesions were successfully identified. Figure 5 shows side-by-side comparison of CT and PET scans in a patient with a recurrent stromal tumor before and after tyrosine kinase inhibitor therapy. A percutaneous39 or endoscopic40 biopsy has been described as being successful in the diagnosis of GISTs but is unable to distin-

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guish between benign and malignant tumors. Although a preoperative diagnosis may be possible, it usually adds little to the management of primary neoplasms. The only potential value for a preoperative biopsy is in patients with locally advanced or metastatic disease, in which case neoadjuvant therapy may be considered. Finally, a percutaneous biopsy carries the risk of pseudocapsule rupture and intra-abdominal dissemination.

SURGERY Surgical therapy is governed by 3 principles: complete resection, if possible, without violation of the pseudocapsule, debulking (including potential resection of liver metastases), and symptom palliation. GISTs tend to be discrete masses surrounded by a pseudocapsule, which, despite a large tumor size, may not invade adjacent organs. Large GISTs often demonstrate a liquefied, necrotic center, which is characteristically seen on a preoperative CT scan. The central necrosis often makes the tumor itself fairly fragile and prone to rupture during operative manipulation. Sizable tumors may become saprophytic and may parasitize the blood supply from surrounding structures such as omentum. Therefore, careful dissection of tissue planes should be performed to avoid excessive blood loss, and ligation of nonanatomical vessels is usually necessary. Some GISTs will invade surrounding structures, which then requires en bloc resection of involved organs. In many cases, invasion may be hard to determine by either preoperative imaging or even intraoperative inspection; therefore, erring on the side of en bloc resection is preferred over the risk of violating the tumor (Fig 6). Spreading of the disease through the lymph nodes is uncommon in GISTs; thus, routine lymphadenectomy is not necessary. Because surgical therapy remains the only opportunity for a cure and/or palliation of symptoms, aggressive resection or debulking is encouraged, even in the face of metastatic disease.41,42 Similarly, an aggressive surgical approach to peritoneal and hepatic metastatic disease is also indicated.43,44 However, new chemotherapeutic treatment options may alter this philosophy. ESOPHAGUS Unlike tumors at other sites along the GI tract, the majority of mesenchymal tumors of the esophagus are likely to be entirely smooth muscle in origin and probably represent true leiomyomata. This is in contrast to other segments of the GI tract in which leiomyomas are rare, and GISTs are more common.45 This smooth muscle variant is almost always benign. Therefore, benign stromal tumors occur 10

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times more frequently than malignant GISTs in the esophagus. Mesenchymal tumors are a rare tumor of the esophagus comprising only 1% to 2% of all tumors at this site. However, they are the most common benign tumor of the esophagus. Esophageal stromal tumors can occur at any age. The peak incidence for benign tumors of the esophagus is in the fourth to sixth

FIGURE 6. Gastric stromal tumor that occupied virtually the entire left upper quadrant, resected en bloc. It demonstrated invasion into multiple adjacent organs including the pancreas, spleen, and omentum. A, In situ tumor. B, Gross pathologic specimen.

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decades of life, whereas malignant tumors are most likely in the sixth and seventh decades of life. Eighty percent to 90% of all esophageal GISTs arise in the distal two thirds of the esophagus. Dysphagia and pain are the most common symptoms of esophageal GISTs. Weight loss will be seen in more than 50% of patients with malignant GISTs.46 A diagnosis can be difficult because these GISTs share symptoms with the more frequently seen esophageal carcinoma. Contrast swallow, endoscopic visualization and endoscopic ultrasonography and CT scanning are all useful adjuncts to the diagnosis of esophageal stromal tumors. Leiomyomas tend to reside within the esophageal wall and, as such, have a classic smooth appearance on a barium swallow test (Fig 7). On endoscopy, the intrusion into the lumen of the esophagus appears smooth and is covered with normal intact mucosa. Ultrasonographically, these lesions are characteristically discrete and have easily identifiable margins.32,33 CT scanning has the advantage of identifying the tumor in relation to surrounding structures and can assess for the rare case that involves metastatic disease. Surgical management of esophageal stromal tumors differs markedly from that applied to other segments of the GI tract. Benign leiomyomata arising in an intramural location may be addressed by simple enucleation, with care being taken to avoid violation of the mucosa. This is most frequently via a transthoracic approach. Leiomyosarcomas or very large tumors require more extensive segmental excision to achieve clear margins. Because of local invasion, transhiatal esophageal resection is less frequently appropriate than is either a right or a left thoracotomy. STOMACH More than 50% of all stromal tumors of the GI tract arise in the stomach. GISTs are most frequently found in the body of the stomach but may occur anywhere within the organ. Although benign tumors remain more common, they outnumber malignant GISTs by a ratio of only 1.4:1. Gastric GISTs occur most frequently between the fifth and seventh decades of life.47 The symptoms of gastric GISTs, as with tumors at other sites along the GI tract, usually include bleeding, abdominal pain, a palpable mass, and weight loss.47-49 GI bleeding may be seen with either hematemesis or melena but is usually self-limited and is seldom exsanguinating. The workup is usually directed by presenting symptoms, is similar to that used for other gastric lesions, and includes a barium upper GI series, upper endoscopy, endoscopic ul-

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FIGURE 7. Barium swallow test demonstrating the smooth luminal-encroaching defect of an esophageal leiomyoma.

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trasound, and CT scanning. Because upper GI bleeding or obstructive symptoms are common, the evaluation usually begins with upper endoscopy or an upper GI barium series. Successful preoperative identification depends on the nature of the tumor in relation to the gastric wall. Endogastric polypoid or ulcerated lesions will be well identified and located by both barium studies and esophagogastroduodenoscopy. Often, intramural lesions will have an overlying intact mucosa very similar to those seen in the esophagus. An endoscopic biopsy frequently will reveal only normal mucosal tissue. Because large eccentric tumors usually present with bleeding, endoscopy may demonstrate a small benign appearing ulcer with evidence of previous hemorrhaging (Fig 2). Exophytic lesions that do not demonstrate ulceration may not be identified on either endoscopic or barium contrast studies; however, if the GIST is large enough, extrinsic compression may be seen. CT scanning is the most useful technique for identification of gastric GISTs: it can identify tumors greater than 2 cm, characterize central necrosis, and simultaneously assess for metastatic disease.36,37 Large stromal tumors arising from the stomach, however, are often indistinguishable from large tumors originating from other organs, especially from the left lobe of the liver (Fig 4). Surgical management of gastric stromal tumors is largely determined by the tumor’s location on the stomach. Often, even large GISTs are attached to the stomach with a small stalk only a few centimeters long. Such tumors can be removed with only limited resection of the gastric wall (Fig 8). Generally, a 2- to 3-cm margin along the gastric wall is acceptable, and larger margins have not been shown to improve survival rates.50 More extensive gastrectomy may be indicated by the location of the tumor on the stomach or by more extensive gastric wall involvement. Occasionally, stromal tumors will invade surrounding organs, which requires extensive en bloc resection, including distal pancreatectomy and splenectomy, colectomy, and left liver lobectomy (Fig 6). SMALL BOWEL After the stomach, the small intestine is the next most common location for GISTs: approximately 90% of these tumors are found within the ileum and jejunum. Duodenal GISTs are less common. As with stromal tumors of the stomach, patients with small bowel GISTs tend to be older; the peak incidence is in the sixth decade of life.51,52

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Symptoms of small bowel GISTs are often subtle and indistinguishable from other small bowel neoplasms. GI bleeding is common, often chronic, and may be difficult to diagnose on routine endoscopy and contrast studies. The role of enteroscopy or capsule endoscopy has yet to be defined but may prove useful. As with gastric GISTs, CT is the most useful examination for identifying the tumor (Fig 9). Duodenal stromal tumors in a periampullary position will often present with obstructive jaundice and will be visualized on upper endoscopy. Bowel obstruction may occur as a result of luminal compromise from the tumor itself or intermittently as a result of intussusception of the tumor into the small bowel. The workup of obstructive symptoms may include a number of diagnostic tests; however, the diagnosis is often made at surgical exploration. Segmental resection of the involved portion of the small bowel with primary anastomosis is the treatment of choice (Fig 10). Complete en bloc excision of the tumor, as with gastric GISTs, is required; however, extensive resection of lymph node tissue is not necessary. Small, incidentally found tumors should also be resected because of the difficulty in predicting their biological behavior. As with other periampullary tumors, a pancreaticoduodenectomy may be necessary for tumors arising in the duodenum.

FIGURE 8. Pedunculated gastric stromal tumor (A) before resection and (B) after resection showing longitudinal closure of the limited gastric wall resection.

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FIGURE 9. Computed tomographic scans of jejunal (A) and duodenal (B) gastrointestinal stromal tumors (GISTs). The jejunal GIST is seen just distal to the ligament of Treitz. Note the necrotic center of each GIST.

COLON AND RECTUM GISTs of the colon and rectum are most frequently encountered in the sixth decade of life. The most common presenting symptoms of colonic GISTs are pain, a palpable mass, and GI bleeding. Rectal GISTs are more likely to have GI bleeding or symptoms of tenesmus and may be felt as a mass on a rectal examination. Colonic GISTs are

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FIGURE 10. Gross pathologic specimen of resected jejunal gastrointestinal stromal tumor. The necrotic, hemorrhagic center is easily identified. This tumor demonstrates an exophytic stalk off the small bowel.

more commonly found on the left side of the colon, although they are found throughout the large intestine and appendix.53,54 Segmental resection without an extensive lymphadenectomy remains the treatment of choice.

OUTCOME RECURRENCE Recent series have reported longitudinal experiences with GISTs. In addition, a number of older series reporting experiences with leiomyomas and leiomyosarcomas of the GI tract most probably reflect experiences with GISTs because stromal tumors likely represent the majority of these tumors. GISTs demonstrate a predictable pattern of recurrence and metastasis. Twenty percent to 50% of patients who undergo complete resection of GISTs will demonstrate a recurrence.55-60 Most recurrent disease is identified within the first 2 years, but a number of cases of late recurrence have been reported. The most frequent site of recurrence of GISTs is the liver (Table 4), followed by a local recurrence at or near the site of resection (Fig 11), and disseminated intraperitoneal disease. Because no true en-

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TABLE 4. Sites of First Recurrence in Patients with Primary Disease Who Underwent Complete Resection Recurrence Liver Any Only Local Any Only Liver ⫹ local Extra-abdominal Any lung Any bone

n

% of Total Recurrences

17 12

63 44

14 9 4

52 33 15

2 2

7 7

(Courtesy of DeMatteo R, Lewis J, Leung D, et al: Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 231:51-58, 2000. Copyright Lippincott Williams & Wilkins.)

FIGURE 11. Computed tomographic scan demonstrating the local recurrence of a gastric stromal tumor several months after resection (white arrow).

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capsulating margins exist, a local recurrence is likely due to an unidentified grossly positive margin at the time of resection. Interestingly, microscopic margin status does not appear to predict a recurrence.55 In addition, violation of the pseudocapsule with spillage of necrotic tissue is likely to be associated with a local or disseminated intra-abdominal recurrence. Rarely, lymphatic metastases have been reported. REOPERATION Not infrequently, the recurrence of GISTs (or even disseminated disease present at the index operation) presents as individual discrete nodules amenable to resection.57 Traditionally, aggressive reresection of recurrent abdominal disease has been warranted because effective adjuvant therapy was lacking and reoperation seemed to confer a survival benefit. In addition, liver resection for metastatic (initial or recurrent) disease has been shown to be safe and also improves the probability of survival.41,44 This management paradigm, however, is being reconsidered with new effective chemotherapeutic options. SURVIVAL Historically, 5-year survival rates after complete resection of a GIST range from 30% to 65%. A number of predictors of survival have been identified, including tumor size,31,41,47,48,55,57,60 mitotic rate,14,24,48,51 complete resection,41,48,52,55,57 tumor capsule violation,41 and tumor site.31,41 Size and mitotic rate remain the most important predictors of survival because they are the primary determinants of malignant behavior of these tumors. Most studies confirm that a size greater than 10 cm confers a poorer prognosis; however, a size greater than 5 cm denotes intermediate risk. Mitotic rates of 5 to 10 mitoses per high-powered field denote an increased risk of malignant behavior. These are the 2 main prognostic indicators incorporated into risk assessment in a recent consensus statement (Table 2).12 In addition, immunohistochemical measures of heightened mitotic activity (such as the presence of PCNA and Ki-67) have been shown to carry a poorer prognosis. Esophageal tumors tend toward benign behavior and carry a better prognosis (Fig 12); however, for many historical studies, these data may represent true esophageal leiomata.45,46 Previously, adjuvant therapies have not demonstrated a survival benefit. However, older studies do not distinguish between leiomyosarcomas and true GISTs. Newer chemotherapy trials with imatinib mesylate (Gleevec), a targeted tyrosine kinase receptor, may have a profound effect on survival. However, long-term data are lacking on

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Figure 12. Kaplan-Meier survival curves of patients with gastrointestinal stromal tumors from the Johns Hopkins surgical series (Log-rank test for significance): A, cumulative survival by site (P ⫽ .02); B, cumulative survival by size (P ⫽ .03 vs size <10 cm). (Courtesy of Efron DT, Lillemoe KD, Cameron JL, et al: Surgical management of gastrointestinal stromal tumors: A single institution 33-year experience. Gastroenterology 120:A41, 2001. Used with permission from the American Gastroenterological Association.)

a significant number of patients to determine the overall survival benefit, if any, to this regimen.

ADJUVANT THERAPY PERITONEAL CHEMOTHERAPY Until recently, traditional chemotherapy or radiotherapy regimens have not been effective for GISTs. Some interest, however, has been expressed in the use of intraperitoneal chemotherapy. One study combined aggressive surgical resection with intraperitoneal mitoxantrone. Although this has no effect on survival or hepatic disease,

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it may lower the peritoneal recurrence rate and has an acceptable toxicity profile.43 This finding suggests a potential role for reducing peritoneal seeding at the primary operation. There is also interest in using hyperthermic intraperitoneal chemotherapy, thereby enhancing the local-regional cytotoxic effect of the agents; several studies are in progress.9,61 Regional chemoembolization of hepatic metastases has also been reported with some success.62 IMATINIB MESYLATE Among the most exciting developments in the treatment of all cancer has been the successful employment of targeted cell receptor chemotherapy for certain malignancies, including GISTs. The “gain of function” mutation in the c-KIT receptor, which is seen in virtually all GISTs, makes this an ideal target for receptor blockade. Imatinib, initially developed to treat myelogenous leukemia, blocks the adenosine triphosphate binding site at the intracellular domain of the kinase domain of the c-KIT receptor, thereby inhibiting signal propagation.63 Proof of efficacy was first demonstrated in a case report64 of a patient with advanced liver and peritoneal disease who demonstrated a near-complete response to oral therapy. A subsequent phase 1 trial of 40 patients showed that 18 patients had a partial response at a dose range of 400 to 1000 mg/d. Side effects were mild and well tolerated.65 In addition, in a phase 2 trial of 147 patients receiving either 400 or 600 mg of imatinib daily, 54% demonstrated radiographic evidence of a response overall, and no significant difference was seen between dosing groups.66 Two large randomized trials have failed to identify differential survival or tumor responses between low- and high-dose treatment (400 vs 800 mg daily)67,68; however, the higher dose appears to prevent progression of disease during therapy in a small percentage of patients (6%).67 The optimal length of treatment is not yet established, and a trial of patients with GISTs and no evidence of advancing disease is currently under way to compare continued versus interrupted treatment with imatinib. Until this is resolved, continuous therapy is warranted. Neoadjuvant therapy with imatinib has, as yet, not been established. A complete response to imatinib alone is rare, but a number of articles69,70 suggest that sufficient downstaging may occur and, thus, may allow resection of previously inoperable lesions. Surgery remains a key component of therapy. A randomized study is ongoing at present. Clearly, some GISTs demonstrate tumor progression, despite imatinib therapy. Not all stromal tumors demonstrate gain of function mutations in KIT, a characteristic that appears to correlate with

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the response to imatinib therapy.71,72 Furthermore, patients with c-kit mutations at exon 11 are more likely to benefit from imatinib therapy than are those who demonstrate mutations at exon 9. Only a small percentage of patients who demonstrate mutations in plateletderived growth factor receptor alpha have a response to imatinib therapy.72 Options remain limited for patients whose tumors progress during imatinib therapy. Crossover to higher dose therapy (from 400 mg daily to 800 mg daily) may be of benefit in some patients for both a potential partial response and disease stabilization, which may be seen in as many as 23% of patients; however, long-term follow-up is pending.68,73 More recently, the multitarget tyrosine kinase inhibitor SU11248 has shown promise in a phase 1 study74 as an alternative targeted therapy providing disease regression or stabilization in 11 of 18 patients. This has prompted randomized study of its effec-

FIGURE 13. Proposed decision tree for treatment of gastrointestinal stromal tumors. Abbreviations: GIST, Gastrointestinal stromal tumor; CT, computed tomography; PET, positron emission tomography; CA Rx, cancer therapy. (Modified from the National Comprehensive Cancer Network: Sarcoma Guidelines, http://www.nccn.org/, accessed 2004.)

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tiveness in patients with progression during or intolerance of imatinib therapy. A recent consensus statement from the National Comprehensive Cancer Network has proposed an algorithm for the management of GISTs.75 Figure 13 streamlines the basic approach to the management of GISTs. Clearly, at present, surgery remains the mainstay of therapy, but new targeted adjuvant and neoadjuvant therapies may prove vital in the management of these neoplasms.

CONCLUSION Over the last decade, GISTs have gone from a surgical obscurity to a tumor of extreme interest, not only to surgeons but also to oncologists. Although these tumors still represent a challenge in terms of diagnosis and surgical management, they can generally be managed by minimal to wide surgical extirpation. The role of targeted molecular therapy for these tumors, based on the understanding of the molecular events that have been well defined in tumor formation, has made GISTs the paradigm for molecular cancer therapy. Whether, in the end, the development of such specific tumor therapy will provide effective neoadjuvant, adjuvant, or therapeutic treatment of advanced disease will only be known after long-term studies. In the meantime, the advances in the understanding of the pathogenesis and treatment of these tumors represent one of the most exciting developments in all of cancer therapy in recent years.

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