The role of surgery in the management of gastrointestinal stromal tumors (GISTs) in the era of imatinib mesylate effectiveness PDF

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ARTICLE IN PRESS Surgical Oncology 14 (2005) 75–84 www.elsevier.com/locate/suronc Mini review The role of surgery in the management of gastrointestinal stromal tumors (GISTs) in the era of imatinib mesylate effectiveness Nikolaos Kosmadakis,1, Evangelos–Efstathios Visvardisa,1, Panagiotis Kartsakli...

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ARTICLE IN PRESS

Surgical Oncology 14 (2005) 75–84 www.elsevier.com/locate/suronc

Mini review

The role of surgery in the management of gastrointestinal stromal tumors (GISTs) in the era of imatinib mesylate effectiveness Nikolaos Kosmadakis,1, Evangelos–Efstathios Visvardisa,1, Panagiotis Kartsaklis, Maria Tsimara, Alexandros Chatziantoniou, Ioannis Panopoulos, Palli Erato, Paul Capsambelis a

Department of Surgery, General Hospital of Zakynthos ‘‘Aghios Dionyssios’’, Peripheral National Health System ‘PESY’ of Ionian Islands, Zakynthos 29100, Greece

Abstract Surgical resection is the treatment of choice for the gastrointestinal stromal tumors (GISTs). In the literature, the 5-year patient survival after surgical resection, ranged from 48 to 80%, before the era of imatinib mesylate and the exploration of the prognostication criteria. Imatinib mesylate targets an intracellular signaling molecule of the natural history and malignant development of GISTs, and increased the 5-year survival rate, after the resection of primary low-risk GISTs, to similar values to the normal population. For high-risk GISTs, current knowledge which is still under expansion, show major improvement at the 1-year survival rate of more than 90% versus less than 50% before imatinib era. After surgical resection, for both low and high malignant potential GISTs, a closed control directed to the early identification of confined resectable recurrences, is required. This paper assesses the current knowledge of GIST management, motivated by a case of patient with intermediate risk GIST. r 2005 Elsevier Ltd. All rights reserved. Keywords: Surgery; Management; Imatinib; Glivec; Gastrointestinal stromal tumor; Gist; c-kit; Mini review

1. Background Gastrointestinal stromal tumors (GISTs) belong to the group of soft tissue sarcomas, and are a subset of a broad category of mesenchymal tumors of the gastrointestinal (GI) tract, which also includes leiomyomas, leiomyosarcomas, and schwannomas. Grossly, GISTs are grey–white, smooth, well-circumscribed lobulated, extraluminal or intramural tumors, which arise within the muscularis propria of the GI tract wall and contain a pseudocapsule. They may occur anywhere along the length of the digestive tract from the esophagus to the anus. Approximately 60–70% of the GISTs arise in the Corresponding author. Tel. +302695059100, +302695059215; fax: +302695024143. E-mail address: [email protected] (N. Kosmadakis). 1 Equal authorship.

0960-7404/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.suronc.2005.05.002

stomach, 20–30% in the small intestine, 5% in the colon and in the rectum and less than 5% in the esophagus. Sometimes GISTs develop outside the intestinal tract, in the abdominal cavity. They account for approximately 1–3% of gastric neoplasms, 20% of small bowel tumors and 0.2–1% of colorectal tumors [1]. The term GIST was first used by Mazur and Clark in 1983, and includes a heterogeneous group of nonepithelial neoplasms with spindle or epithelioid cells, which may display myogenic features (smooth muscle GISTs), neural attributes (gastrointestinal anatomic nerve tumor), or characteristics of both muscle and nerve (mixed GISTs), or may lack differentiation (GISTs not otherwise specified)[2]. The interstitial cells of Cajal, the intestinal pacemaker cells, may share the same non-neoplastic progenitor cells with GISTs, having characteristics of both smooth muscle and neural differentiation on ultrastructural examination [3]. Most of GISTs (50–72%) stain positive

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for CD34, but the more specific diagnostic criterion is the immunohistochemically determined KIT (CD117) [4]. More than 90% of GISTs, and the interstitial cells of Cajal, express KIT, which is the receptor tyrosine kinase product of the c-kit proto-oncogene, and is found universally phosphorylated in GISTs, due to activating, gain-of-function mutations in the c-kit proto-oncogene. Men and women are equally affected, and most GISTs occur in older patients, typically between the ages of 50–60. Sporadic instances are rare before the age of forty [5]. However, GISTs can be familial, thus can be present in younger patients [6]. The human c-kit gene, located on chromosome 4, encodes a transmembrane receptor tyrosine kinase called KIT, which is expressed by the interstitial cells of Cajal, hematopoietic cells, melanocytes, and mast cells. The natural ligand for KIT is known variably as KIT ligand, stem cell factor, Steel factor, or mast cell growth factor. Binding of KIT ligand induces dimerization and autophosphorylation of KIT, which in turn results in activation of a cascade of intracellular proteins that promote cell survival and proliferation [7,8]. Sequencing of c-kit complementary DNA from human GIST cells has demonstrated a high frequency of mutations that lead to constitutive activation of the KIT tyrosine kinase in the absence of stimulation by its physiologic ligand, causing uncontrolled stimulation of downstream signaling cascades with aberrant cellular proliferation and resistance to apoptosis. The most frequent mutations were identified in exon 11 (juxtamembrane domain) of the gene and resulted in activation of the KIT receptor [9]. Mutations in other regions of the c-kit gene, including exons 9, 13, and 17, have also been reported, although they occur at a much lower frequency [10,11]. Activating mutations in c-kit have also been elucidated in germ cell tumors, myelofibrosis, chronic myelogenous leukemia (CML), and mastocytosis [12]. GIST has also been shown to contain a variety of chromosomal abnormalities ([13], and references therein). A small percentage [o5%] of otherwise typical GIST, lack c-kit mutations and thus no c-kit/CD117 protein could be detected immunohistochemically. Such CD117-negative tumors have often mutations in platelet-derived growth factor receptor a (PDGFRa), which is another tyrosine kinase [14]. Complete gross-surgical resection is the current definitive treatment for GISTs. Recurrent disease, however, remains a problem, and recurrent GISTs are often found in the liver or in the form of peritoneal deposits. The preferred treatment for recurrent tumors may still be surgical resection, and the management of GISTs has been effectively supported by the specific molecular inhibitor imatinib mesylate (Gleevecs or GlivecTM, Novartis), for both unresectable diseases as well as adjuvant therapy after the resection of primary GISTs [15–17].

2. Clinical presentation of GISTs Early stage GISTs, often do not have any symptoms. The mean age of patients has been reported to be around 60 years (range 22–79 years). The most frequent clinical manifestations are occult gastrointestinal bleeding, fatigue due to anemia, anorexia, vomiting, dyspepsia, a palpable mass and mild abdominal pain. Because of the non-specific symptoms, GISTs are delayed diagnosed, with a mean duration of symptoms of 6 months before presentation. Over 5% of patients have more than one complaint or physical findings [18,22], without significant correlation of these symptoms to the prognosis [19]. These symptoms usually occur with larger tumors, but even small tumors can undergo necrosis and ulceration, thereby producing pain or bleeding. In a study by Nishida et al. of 271 patients with GIST, two-thirds of patients had symptoms that correlated with tumors size. Tumors larger than 3 cm were more likely to demonstrate necrosis and ulceration than tumors less than 3 cm [20]. Visceral obstruction is rare. In the study by Burkhill et al. of 61 patients who underwent CT scans following diagnosis, one developed small bowel obstruction, one developed unilateral renal obstruction, and there were no cases of bile obstruction [21]. GIST appears to occur with increased frequency in patients with a history of neurofibromatosis type I, as well as hyperpigmentation [11,22].

3. Diagnosis and malignant behavior of GISTs True GISTs can be recognised from other tumors by histological analysis and the detection and elucidation of KIT (CD117) and CD34 expression [18,22,23]. Biopsy procurement by either percutaneous or endoscopic techniques is acceptable for tumors that are clearly inoperable or recurrent. For operable disease, biopsy carries the theoretical risk of peritoneal seeding or tumor rupture, thus it seems best to reserve diagnosis, and consideration for inclusion in imatinib mesylate treatment, until after appropriate resection and full diagnostic evaluation of the excised tumor [24]. A mass lesion, organ invasion and distant metastases can be demonstrated by Computed Tomography (CT) and Magnetic Resonance imaging (MRI), which are the most frequent diagnostic imaging studies for the detection and staging of a primary GIST [25]. In a study by Nishida et al. a 1 cm GIST of the jejunum not seen by endoscopy was identified by CT, as well as all 2 cm tumors or greater in size (151 out of 160 tumors) [20]. Since most GISTs have an exophytic growth pattern and arise within the muscularis propria of the stomach or intestinal wall, they are exhibited as dominant masses outside the organ of origin. Dominant intramural and intraluminal masses are less common

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radiologic manifestations. Small tumors tend to appear homogeneous whereas larger tumors (46 cm) frequently show central areas of necrosis or hemorrhage [21]. Levy et al. reported site-specific radiologic features of GISTs, which are very useful to separate GISTs from other tumors. Gastric GISTs commonly demonstrate extension into the gastrohepatic ligament, the gastrosplenic ligament, and the lesser sac, and frequently the bulk of the tumor is seen in an extragastric location. Furthermore, the cavities that develop from central necrosis or hemorrhage in the larger tumors may communicate with the gastric lumen and therefore contain fluid, air, or contrast material. Small intestinal GISTs demonstrate similar features of peripheral enhancement and central areas of low attenuation. They may appear as intramural masses or intraluminal polyps, and may show extension into adjacent mesentery. Encasement of adjacent small bowel, colon, and bladder can also be seen. Anorectal GISTs most commonly present as a well-defined, eccentric mural masses that expand the rectal wall, may contain central areas of hemorrhage, mucosal ulceration and may extend into the ischiorectal fossa, prostate, or vagina. Colonic GISTs are described as transmural tumors that involve the intraluminal and extraserosal surfaces of the colon, and may include hemorrhage, necrosis, or calcification. Esophageal, mesenteric, and omental GISTs may also contain central areas of hemorrhage, necrosis, or cystic change [26,27]. The most common site for GIST metastasis is the liver, followed by peritoneum, whereas ascites formation is very rare. Other sites include retroperitoneum, pleura, lungs, bone, and a cerebral relapse of metastatic GIST has been recently reported [28]. Endoscopic ultrasound would be helpful to distinguish and scrutinize intramural masses, and to evaluate whether a mucosal ulceration is due to sarcoma or due to a non-stromal tumor, to assess pancreatic involvement, as well as to assess involvement in the lower gastrointestinal tract [29,30]. Tumor grade is a major factor with effect on survival and on recurrence. Older terminology of ‘‘benign’’ and ‘‘malignant’’ GIST, or ‘‘leiomyoma’’ vs ‘‘leiomyosarcoma’’ created confusion and more analysed grading systems for GISTs have been proposed. Pierie et al. proposed to classify GISTs as low-grade tumors, presenting 1 mitosis per 10 high-power microscopic fields (HPF), and high-grade tumors, with more than 1 mitosis per 10 HPF. Patients with tumors larger than 5 cm and/or subsequent high-grade histological features are at very high risk for recurrence and subsequent mortality [31]. Kwon [32] categorized tumors as malignant GISTs when mitoses are more than 5 per 50 HPF and the size larger than 5 cm, or as benign GISTs when the mitoses are 5/50 HPF and the size is less than 5 cm.Such benign GISTs had not recurred or metastasised. Howe et al. showed that patient age, sex, tumor size, tumor grade, histologic type, general summary

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stage, nodal status, and whether cancer-directed surgery was performed, were significantly correlated with disease-specific survival. In a multivariate analysis, the tumor size of less than 5 cm, a leiomyosarcoma histology and localized disease were found to be significant favorable prognostic factors [33]. Fletcher et al. [34] and within the consensus approach to diagnosis and morphologic prognostication of GIST supported by the National Institutes of Health, USA, described a scheme for estimating metastasis risk, based on tumor size and mitotic count. According to this scheme, GISTs were divided into very low risk (size o2 cm and mitoses o5 per 50 HPF), low risk (size 2–5 cm and mitoses o5 per 50 HPF), intermediate risk (size 2–5 cm and mitoses 6–10 per 50 HPF, or size 6–10 cm and mitoses o5 per 50 HPF) and high risk (size 6–10 cm and mitoses 45 per 50 HPF, or size 410 cm and any rate of mitoses, or any size of tumor and mitoses 410 per 50 HPF) [34]. Yan et al. [35] have recently assessed the prognostic criteria of GISTs and reported that the tumor location did not have a significant impact on survival, though earlier studies have concluded that small intestine GISTs behave more aggressively than tumors from the stomach [19,36]. Additionally the tumor size, the peritoneal cancer index, the completeness of cytoreduction, along with the cytologic atypia, necrosis, invasion and number of mitoses had a significant impact on the prognosis of GIST at all locations. Bucher et al., proposed a new classification of GISTs, according to their malignant potential and in agreement to other recent studies. The scale composes of five minor criteria (tumor size X5 cm, mitoses X5/50 HPF, presence of necrosis, infiltration of adjacent mucosa or serosa, and Ki-67 immunostain index X10%), and two major criteria (presence of either lymph node invasion or GIST metastases). GISTs harbouring fewer than four minor criteria, are considered of low malignant potential (5-year survival in patients with small intestinal stromal tumors higher than 92%), whereas GISTs with four or five minor criteria or one major criterion are considered of high malignant potential, and exhibited a 5-year survival of less than 20% [37].

4. Surgical resection of GISTs The principal treatment of a patient with a primary GIST is complete surgical resection. The tumor is often fragile, especially if it is large or there is extensive intratumoral hemorrhage or necrosis. Therefore, meticulous surgical technique is necessary to avoid intraoperative tumor rupture, which is associated with a poor prognosis [32]. GISTs tend to protrude from the tissue of origin and displace surrounding structures, and therefore a wedge or segmental resection of the underlying organ is required. Consequently, negative surgical

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margins are usually attained. The status of the microscopic margin of resection does not affect survival and may not be as important as whether the tumor sheds cells directly into the peritoneal cavity [15,19]. Lymphadenectomy is not performed routinely in patients with GIST because lymph node metastases are rare and appears to be a late event in the history of a malignant GIST [38]. Yao et al. [29] advocate to remove the perigastric nodes and omentum in gastric GISTs, whereas for small bowel lesions it is recommendable to remove the adjacent mesentery, and for colon and rectal lesions the mesocolon or the mesorectum. DeMatteo et al. [15] reported that 80 out of 93 patients with primary GISTs (86%), were able to undergo complete surgical resection of their disease, and their 5-year diseasespecific survival rate was 54% [15]. Patients who could not undergo complete resection had a median survival of only 12 months. Former studies of series of patients with much longer follow-up showed similar findings, and elucidated that patients with tumors larger than 10 cm, had a 5-year survival rate of less than 20% [1,39]. In the retrospective study of 69 patients by Pierie et al. [31] evaluating tumors with a 57% incidence of more than 1 mitosis/10HPF, the mean 5-year survival rate was 42%, after complete resection of the proliferating tumors, compared with 9% after incomplete resection. Other retrospective studies, have also associated the complete surgical resection of primary GISTs with a 5year survival rate of 42–70%, and highlighted the relation between an early stage GIST, at diagnosis and the completeness of it’s resection, to the prediction of a longer overall survival [17,40,41]. Prognosis of low risk (low malignant potential) GIST after complete resection is excellent [37]. However highrisk (high malignant potential) GISTs have a high rate of recurrence. The follow-up of patients is a combination of clinical and appropriate imaging studies directed to the early identification of confined resectable relapses [42]. The first site of distant recurrence in GIST is typically within the abdomen and involves the liver, the peritoneum, or both. In studies with multivariate analysis of post-recurrence survival, a longer length of the disease-free interval, between the initial operation and recurrence, predicts a longer survival after recurrent resection. In the studies by Ng et al. a 10% of patients who underwent complete resection of the primary tumor, and were disease free after a median follow-up of 68 months, showed a median time to recurrence of approximately 1.5–2 years [15,39,43]. Those patients with isolated liver metastases showed a trend toward better survival to all other abdominal recurrences. DeMatteo et al. showed that from 131 patients with liver metastases, hepatic resection of all gross disease was possible in 26%. The 1- and 3-year survival rates were 90% and 58%, respectively, and the disease-free interval from the primary resected GIST was a

significant predictor [44]. Others had similar results [45]. Nearly all patients’ disease subsequently recurs after hepatectomy, with the liver being the most common site of relapse. Prognostic factors that are associated with improved survival after relapse are a disease-free interval of 418 months, recurrence limited to either peritoneal cavity or liver and complete resection of metastatic disease [46]. The recurrent peritoneal GISTs, as in the case of liver recurrences, can be effectively resectable, and of good prognosis, in patients with a long disease-free interval. The recurrent peritoneal nodules may be limited to the region of the primary tumor or located diffusely throughout the abdomen, resting on the surface of the intestine, omentum, mesentery, or abdominal wall, and therefore they can often be removed with limited, seldom curative resections [38].

5. Imatinib mesylate therapy Malignant GIST has been highly refractory to conventional cytotoxic therapy [5,40]. The selective small-molecule tyrosine kinase inhibitor, imatinib mesylate (GlivecTM, or Gleevecs, Novartis) specifically inhibits the Abl and Bcr–Abl fusion protein (the tyrosine kinase activity responsible for the pathogenesis of chronic myelogenous leukaemia, CML), the PDGFR (platelet-derived growth factor receptor), and c-kit tyrosine kinases. Imatinib mesylate treatment led to apoptotic death of GIST cells [47–48]. It is well absorbed after oral administration, with a half-life of approximately 16 h in the circulation [49]. Initial clinical trials targeted patients with CML and shortly thereafter, clinical trials were initiated in GIST patients [16,24,50,51]. In an expanded phase II trial, in patients with unresectable or metastatic CD117-positive-GISTs, who were treated with a dose of 400 or 600 mg/day, imatinib mesylate demonstrated minimal toxicity and substantial activity [50]. The patients either had not received prior radiotherapy, or tumor embolization, or had received chemoth...