Gastrointestinal stromal tumors

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Gastrointestinal stromal tumors

I. Popescu, S. Andrei
Referate generale, no. 2, 2008
* Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
* Center of General Surgery and Liver Transplantation

Gastrointestinal stromal tumors (GIST) belong to the group of primary mesenchymal tumors of the digestive tract wall, along with smooth muscle neoplasms, neural tumors, lipomas, vascular tumors and other rare mesenchymal tumors (table 1), the differential diagnosis between these neoplasias being essential for their management (1).
GIST's are rare tumors of the gastrointestinal tract, compared to carcinomas (only 0,1% to 3% of the GI neoplasms, 5000 new cases per year being diagnosed in the United States of America (2)), but they represent the most common non-epithelial (mesenchymal) tumor of the digestive tract (1, 3). Since this category of neoplasias was recently defined, very few population-based studies are available at this moment. One of these studies established an annual incidence of 14,5 per million, and a prevalence of 12,9 per million population in Sweden (4).
GISTs are found in the stomach in 47-60% of cases, less commonly in the intestine (30% in the small bowel and 5% in the colon and anorectum), rarely in the esophagus (2%) and occasionally outside of the gastrointestinal tract (mesentery, omentum or retroperitoneum) (1, 5, 6).

In 1983, Mazur and Clark are the first medical authors that used the term GIST to name a heterogeneous group of nonepithelial neoplasms composed of spindle (70%), epithelioid (15%), or mixt spindle + epitheliod (15%) cells, which display a range of differentiation (7).
For a long time GIST was regarded as a smooth muscle neoplasm, but immunohistochemical studies in the 80's demonstrated that these tumors do not show complete differentiation toward this cellular line (8). Actually it is believed to originate in an intestinal pacemaker cell called the intestinal cell of Cajal (9) and may have either well- developed or incomplete myoid, neural, autonomic nerve/ganglionic differentiation, or mixed myoid + neural differentiation, or may remain undifferentiated (10). It is now accepted by most experts that there are no truly benign GISTs, the concept "risk of malignant behavior" being emphasized to describe their evolution, according to which GISTs are classified in tumors with low-risk or high-risk to neoplasia, based in two important prognostic factors: the size of the tumor and the mitotic index.
In 1998 was identified the expression of the cell-surface receptor KIT (CD117) as marker of GIST, and mutations in the c-kit gene were established as initiators of the malignant process (11). The gastrointestinal autonomic nerve tumor (GANT) is a morphologic variant of GIST which was considered for many years an alternative diagnose for stromal tumors that exhibit a significant neural differentiation (12).
With the beginning of the third millennium started a new era for the management of GISTs, in 2000 being introduced the treatment with imatinib (a tyrosine kinase inhibitor), which is now the standard chemotherapy for advanced or metastatic tumors (13), and changed the prognostic of this illness, about 80% of the patients treated with imatinib having at least a stabilization of their disease. (14) The surgical treatment remains the standard therapy for GISTs that can be resected with negative margins (13).
There is a great interest in the medical world for this topic, so that a Consensus Meeting for the Management of GISTs was held in Lugano on 20-21 March 2004 under the auspices of ESMO and established thirty consensus points regarding the diagnosis, imaging and therapy of these tumors in order to define the guidelines for the medical practice all over the world, and the most recent Euro-American Course of Pathology of the Digestive System (Geneva, June 2005) had a special part dedicated to the diagnostic approach in mesenchymal tumors of the gastrointestinal tract, focused on GISTs.
In this article we aim to present the actual approach in the histopathological and immunohistochemical diagnose of GISTs, with a short regard in the molecular biology of this disease, along with a few useful clinical features and therapeutical strategies.

Clinical features
GIST patient's median age at diagnosis is around 60 years, with no significant sex variation (some studies show a slight male predominance), and the tumor size varies between 2 and 30 cm in diameter (12, 15-17), incidental discovery during imaging or surgical intervention for other conditions, or during autopsy being frequently described, especially in small, asymptomatic tumors (18, 19).
The main clinical manifestations are mass-related symptoms and anemia (20), but considering that GIST may arise in every part of the gastrointestinal tract, or even outside of it, the symptoms differ widely depending on the site of origin.
Young women can present with a rare entity: "Carney's triad", that associates gastric GIST, paraganglioma and pulmonary hamartoma, but only 25% of the patients have the complete syndrome (6, 21). Rare familial forms of GIST were described (e.g. Hirota et al. reported a familial syndrome of dysphagia with multiple GISTs (22), as well as GIST in the setting of type I neurofibromatosis (1, 20).
Esophageal GISTs occur rarely and usually go with dysphagia and odynophagia, retrosternal pain, weight loss or upper digestive bleeding (hematemesis) (23).
Upper gastrointestinal hemorrhage (hematemesis or melena) is the main manifestation of gastric stromal tumors, occurring in 40-65% of patients, the cause being the ulceration of the gastric mucosa overlying the tumor (5). Other symptoms may be abdominal pain, palpable abdominal mass, anorexia with weight loss, early satiety, nausea or vomiting (15, 20). Some times gastric tumors of quite large size can remain asymptomatic for a long time, being found inciden-tally during upper endoscopy, as demonstrated in a mass screening for adenocarcinoma in Japan (5).
Small bowel GISTs often present with common complaints such as pain or anemia, and therefore are frequently misdiagnosed. The duodenal localization may complicate with obstruction of the common biliary duct, with jaundice and fever, similar to angiocolitis in cholelitiasis. Other clinical manifestations of small bowel GISTs are intestinal obstruction or perforation with peritonitis (6).
Colorectal GIST's occur rarely, patients experiencing abdominal pain or discomfort, bleeding or intestinal obstruction, plus for the rectal tumors oligoanuria caused by the invasion of the urinary blader (20, 23, 24).
The predilect metastatic station is the liver, but it may envolve other organs too (ovary, lung, bone, peritoneum, soft tissue, etc). Recently were described choroidal and cerebral metastases of a mesenteric GIST which had multiple hepatic metastases too. Unlike carcinomas, GISTs rarely spread to the regional lymphnodes (2, 13, 25, 26).
Patients with hepatic metastases can develop in end-stages hepatic failure with ascitis, edema and jaundice. Retroperitoneal GIST may present lower-extremity edema (15).

Diagnostic procedures
There are no diagnostic laboratory studies, no tumor markers for this type of tumor (5).
Esophageal and gastric GIST's can be diagnosed by upper endoscopy, barium swallow or CT scan. They also have characteristic patterns of echogenicity that are useful for the endoscopic ultrasound (EUS) diagnosis. EUS is useful as well for the preoperative staging of gastric stromal tumors.
The Consensus Meeting for the Management of GISTs (April 2004) recommended CT scan, MRI and PET scanning as imaging techniques for the evaluation of GIST (13). Considering that PET scan and MRI are not widely available, CT scan remains for the moment the imaging modality of choice for patients with abdominal mass or histologically proven GIST, both for diagnose and preoperative staging, as well as for the follow-up after surgery. (27-30) However MRI and PET scan have a few special indications: Dedicated MRI is superior to CT scan in the preoperative staging of the rectal GIST, while PET scanning is recommended for the early evaluation of tumor response to imatinib treatment (reconsideration of surgical intervention for initially anresectable GIST, after imatinib cytoreduction) and in case of equivocal images suspected to be metastatic (13).
Angiography for important digestive bleeding can also detect an intestinal tumor (15).
Irespective of the location of the tumor, the positive diagnosis requires tissue biopsy with histopathological examination and immunohistochemistry.
Differential diagnosis
GISTs are part of a larger family of tumors: mesenchymal tumors of the gastrointestinal tract, the differential diagnosis between them being often difficult based on clinical features or imaging only. Once other classes of tumors (carcinomas, lymphomas, melanomas) are excluded, the pathologist and the molecular studies are the key-parts in the accurate diagnose, with crucial importance for the therapy and prognostic of this patients (1, 15, 20).
Smooth muscle neoplasms: leiomyomas and leiomyo-sarcomas are the most often encountered differential diagnose, GISTs being recently individualized as entity, for a long time anatomopathologists having classified them together (16, 19, 23, 28). Histopathology combined with immunohistochemistry provides the difference, GISTs staining positive for the CD34 antigen and C-kit proto-oncogene in 95-97% of cases. However there are 3-5% of GISTs that stain negative for CD117 and/or CD34, many of them growing outside of the digestive tract and showing epithelioid features, some of these cases being proved to bear mutations in the PDGFRA gene. In this particular situation, molecular examination for KIT or PDGFRA mutations in expert laboratories is highly desirable (13).

Macroscopic features
GISTs are often solitary tumors (except for the cases of type 1 neurofibromatosis with multiple small bowel tumors), arising from the muscular layer of the GI tract rather than from the epithelium (23, 28). They have an exofitic development with protrusion in the peritoneal cavity or in the gastrointestinal tract, often being unencapsulated and friable.
Smaller tumors have an intact overlying mucosa, but larger lesions may present superficial ulcerations with GI bleeding or may rupture at the time of surgical resection, due to the central necrosis (15, 31).
One third of GISTs may present local invasion at the time of diagnose, and up to half of the cases primarily present with metastases (20).
Microscopic features
The diagnosis of GIST still relies on the standard histological examination of Hematoxylin and Eosin staining, 3 categories of tumors being described: spindle cell type (the most common - 70%), epithelioid cell type (20%) and mixt spindle and epithelioid cell type (10%) (1, 5, 12, 13, 15, 19, 20).
The intestinal tumors, either spindle cell or epithelioid type, may present skenoid fibers composed of collagen and with PAS positivity, and some times the appearance may be misleading, the lesions being paraganglioma-like, glomus-tmor-like, myxoid liposarcoma-like or carcinoid-like (1, 13).
GISTs of spindle cell type have a fascicular or a short storiform pattern, being composed of uniform spindle cells with light eosinophilic cytoplasm and oval shaped nuclei with vesicular chromatin. (fig. 1) Stromal hemorrhage or cystic stromal degeneration may represent a prominent feature (13).
The epithelioid type of GIST is composed of round or polygonal cells with eosinophilic or clear cytoplasm and uniform, round-to-ovoid nuclei, exhibiting more frequently a nested growth pattern (1). In the mixt cell type, transition between epithelioid and spindle cells area can be abrupt, well delimitated, or the two cell types may be intermingled (13).
Spindle cell GISTs should be distinguished histologically from: leiomyoma, leiomyosarcoma, schwannoma, and less frequently from: spindle-cell carcinoma, melanoma or angiosarcoma, from Kaposi's sarcoma and inflammatory fibroid polyp. Differential diagnosis with desmoid tumors or an differentiated liposarcoma that infiltrates the gastrointestinal tract is sometimes needed.
Epithelioid GIST should be differentiated on biopsies from: carcinomas (primary or metastatic), lymphomas (large cell anaplastic lymphomas), melanomas, paragangliomas and glomus tumor, and on surgical specimens from other epithelioid intraabdominal tumors, such as PEC-oma and epithelioid angiosacomas.

Figure 1
Figure 2
Figure 3

CD 117 (KIT) is regarded as the confirmatory marker in the diagnosis of GISTs, since these tumors express KIT in up to 95%, regardless of the localization, biologic behavior or histological appearance (32). (fig. 2) However KIT is not tumor specific for GIST, being expressed in tumors arising from intestinal Cajal cells, but also in hematopoietic system's cells, melanocytic cells, germ cells (33, 34), but not in true smooth muscle tumors or neural tumors (5). So not all Kit-positive tumors are GIST, this immunohistochemical marker being expressed by other entities such as: synovial sarcoma, rhabdo-myosarcoma, angiosarcoma, glioma, germinoma, melanoma, fibromatosis or mastocytosis, anaplastic large-cell lymphoma, Ewing's sarcoma (15, 32, 35).
The positive diagnosis of GIST should be based on morphologic grounds, in the specific clinical and imaging context, and not solely on immunohistochemistry, the positive staining for KIT being important especially to differentiate GISTs from other gastrointestinal mesenchimal tumors (1, 5, 15). Imunocytochemical analysis can be performed using material procured by endoscopic ultrasound-guided fine-needle aspiration (36).
Recently was identified a new marker for GIST called DOG1.1 which is highly sensitive and specific for all GISTs, even for those bearing PDGFRA mutation which stain negative for CD117 (37).
Most GISTs express additionally to KIT (CD117): nestin (90%) and CD34 (60-70%). (fig. 3) Other immunohistochemi-cal markers could be positive in some GISTs: smooth-muscle actin (20-40%), h-caldesmon, CD44, vimentin, S-100 protein (<5%), desmin (<2%) and neuron-specific enolase (5, 15, 38, 39), some of them being cited in some papers as prognostic factors: the positivity of CD34 is considered to implicate a poor prognostic, while CD44 is regarded as a good prognostic feature (5). As we mentioned above, GISTs rarely express desmin or S100, but their presence does not exclude the benefit from imatinib treatment (40).
Usually the expression of KIT is pancytoplasmic and positive in at least 90% of the tumor cells, but it may also show membranous staining or focal staining in as little as 5 to 20% of the tumor cells. This fact can be responsible for the rare cases in which KIT is negative on the preoperative small biopsies, but positive in the excision tumor biopsies.
An other important fact to be considered is that a lack of CD117 immunostaining is not sufficient to rule out GIST because there are a small proportion of KIT negative GISTs (3-5%).
Molecular biology of GIST
It is a well known fact that neoplasia is the result of an imbalance between the rate of cell division and growth (cell mass) on the one hand and apoptosis (programmed cell death) on the other. The main role in driving both sides of this imbalance is played by the aberrant cellular signal transduction pathways, tyrosine kinases being the most important group of signaling molecules involved in cellular regulation (41, 42).
In 1987 the human c-kit gene that encodes the receptor tyrosine kinase (kit) was cloned (6). It is an oncogene located on chromosome 4 that is the cellular homologue of the v-kit oncogene of the Herdy-Zuckerman 4 feline sarcoma virus (43, 44).
KIT is a 145 KD transmembrane glycoprotein receptor for SCF which belongs to the type III in the family of receptor tyrosine kinases, that also includes PDGF-R, macrophage colony-stimulating factor and FLT3 ligand (45). There by, KIT activity is important to the development of the interstitial cells of Cajal (from which GISTs originate), hematopoietic progenitor cells, melanocytes, mast cells and germ cells (46).
KIT is composed of 3 regions: an intracellular tyrosine kinase, a juxtamembrane region and an extracellular domain with a ligand binding site (47). The natural ligand for KIT is known as mast cell growth factor, the KIT ligand, stem cell factor, Stell factor. The KIT ligand bindes to the KIT receptor inducing dimerization with activation of kinase activity and autophosphorylation (6, 48). The activated KIT phospholylates signal transduction proteins and so triggers various signaling cascades that promote cell survival and proliferation.
In GIST or hematological neoplasias, KIT is activated independently of the KIT ligand activity due to mutations of the c-kit gene. Gane-of-function mutations in c-kit were first described in the human mast cell line (HMC-1) and than these mutations were associated with mastocytosis, acute myelogenous leukemia, certain types of lymphomas and germ cell tumors (49).
In 1998 Hirota et al (50) were the first to report mutations in exon 11 (juxtamembrane domain) of the c-kit gene in 5 of the 6 cases of GIST examined. The percentage of GISTs with a KIT mutation varies in different studies from 65% (3) to 92% (51) on cDNA based studies and from 27 to 57% in studies using genomic DNA extracted of paraffin tissue (52-55), the majority of them (67-71%) being found in the juxtamembrane domain, involving codons 550-560 of the hot-spot region of exon 11 (47). It may be point mutations (single b-p substitutions) or complex insertions or deletions (53). The juxtamembrane region of c-kit gene has the function to inhibit the dimerization of the KIT receptor in absence of the KIT ligand. All the mutations in the c-kit gene have a similar effect: to disrupt this function allowing ligand-independent receptor dimerization (56-58).
Several studies reported a more aggressive clinical behavior of GISTs that bear an exon 11 mutation (52-54). However, the same type of exon 11 mutation was discovered in small and very low-risk GISTs, suggesting that these mutations appear early in the evolution of the tumor, so that further studies are needed to clarify whether some specific subtypes of exon 11 mutations are responsible for a higher risk of malignant behavior.
Mutations in other regions of c-kit gene were reported later, including exons 9, 13, 17, but with a much lower frequency than exon 11 mutations (59-62). Singer et. al. reported in a study published in 2002 a frequency of 71% exon 11 mutations, 13% exon 9 mutations, 4% exon 13 mutations ad other 4 % exon 17 mutations in a single institution study of GISTs (63).
A few autors described the mutations that may be even more aggressive than those of the juxtamembrane domain - mutation of exon 9 - which determine and altered intracellular signaling (12) and seems to disrupt an diimerization motif in the extracelular domain (59, 60, 62). Other study groups noted that this mutation is associated with small bowel GISTs and with an aggressive malignant behavior (12, 47, 60, 61).
The first point mutation in KIT exon 13 (the kinase I domain), was identified by Lux et al (53) in 2000 and has been observed since that by several other investigators (12, 60, 64). These mutation also results in ligand-independent activation of the KIT receptor, but it is yet unclear if the mechanism involves the spontaneous receptor homodimerisation (65).
Mutations in the Activation Loop of KIT (exon 17) are also rare in GISTs. Some of them (for example N822K and N822H mutation) were found in sporadic GIST (51) and particular D820Y germline substitution has been related to familial GIST (22). The exon 17 mutation cause activation of the kinase domain by an unknown mechanism. A nearby codon mutation in exon 17 that is highly activating the KIT receptor, is not frequently observed in GISTs but is involved in many human malignancies such as mast cell disease, acute myelogenous leukemia, dysgerminoma and seminoma, suggesting that stem cells that give rise to GISTs have other transforming requirements, ensured by different signaling pathways and initiated by different KIT mutations than those that leed to mastocitosis (12).
The theory accumulation of secondary mutations in the progression of GISTs is not sustained by the biological studies: none of the 127 malignant GISTs examined by Heinrich and Corless in a study from 2003 had more than a single mutation (65).
There are 3-5% of GISTs called KIT-wild-type which are negative for KIT gene mutations and recently identified to bear PDGFRA mutations that are inducing an active kinase just like the KIT activated receptor. The activation of PDGFRA gene and the KIT gene seem to be mutually exclusive. The examination of genomic DNA in PDGFRA mutant tumors revealed various mutations in exon 12 (juxtamembrane domain) and exon 18 (activation loop) with the same signal transduction profile as the KIT mutant tumors. The histological morphology of these tumors is generally epithelioid and some studies revealed that they are less sensitive to imatinib than the juxtamembrane mutation of the KIT gene (49).

Special variants of GISTs
Familial GIST
Several families with heritable mutations in the exon 11 of the KIT gene are identified at this point.
The first one reported was a Japanase family with deletion of one or two valine residues in codon 559 or 560 in which three generations were trased and discovered with hyper-pigmentation of perineal skin and multiple benign and malignant GISTs.
Other kindred from Italy, Japan and US were identified to bear a V559A substitution manifested in heritable skin pigmentation of the perineum, axial, hand and face (but not lips and buccal mucosa), skin mastocystosis (urticaria pigmentosa) and multiple GISTs of the stomach or small bowel at early ages (68, 69).
Some earlier reports of multiple intestinal leiomyomas associated with skin hyperpigmentation ± mast cell disease may have been exon 11 mutation of the KIT gene as well (70).
Other reports consisted in: a family from US - mother and daughter with multiple GANT (gastrointestinal autonomic nerve tumor), demonstrated by doctor Hirota to be strongly positive for KIT at immunohistochemistry and to bear an exon 11 mutation of the KIT gene at the molecular studies (71) and another family - mother and sun from France with more than a dozen intestinal GISTs, found to have a substitution mutation in exon 13 of the KIT gene (72).
A family with mutation in the activation loop of KIT (exon 17) was also described by Hirota et al having multiple gastric and intestinal GISTs and complaints of dysphagia due to abnormal esophageal peristalsis (22). Neither of these patients showed pigmentation or mastocytosis suggesting that their mutation does not support melanocyte or mast cell proliferation.
Other GIST variants
An association of gastric leiomyosarcoma, paraganglioma and pulmonary chondroma was described by Carney in seven young women, two of them having all three lesions united under the name of Carney triad. All the cases were unrelated one to the others, these rare combination being sporadic and not familial. The leiomyosarcomas related to Carney triad were gastric tumors with morphological and immunophenotypical features of GIST, diagnosed under the age of 30 years. Only 15% of Carney triad patients are male. The molecular bases of this illness is unknown an preliminary studies suggests that Carney triad associated GISTs do not bear KIT or PDGFRA mutations (21).
Recently Carney and Statakis described a new syndrome that associates multiple paragangliomas (frequently functional) of the neck, mediastinum and retroperitoneum and multifocal gastric GIST. This syndrome appears to be autosomal dominant an equally represented in males and females, but his genetic locus is still unknown (73).
Gastric GIST occur in children outside of Carney triad their molecular origin is still unclear, the data from the few studies realised by now showing that KIT or PDGFRA mutation are much less common than in adult GISTs (74, 75).
Another interesting observation is the occurrence of GISTs in a subset of patients with type I neurofibromatosis (Von Recklinghausen neurofibromatosis). This patients have multifocal gastrointestinal tumors described as autonomic nerve tumors, leiomyomoas or stromal skenoid tumors upon the time, but with recently documented KIT positivity (76). Why GISTs appear only in a minority of neurofibromatosis type I patients (approx. 7%) is yet to be revealed.
Evolution and prognosis of GIST
There is a consensus in considering the evolution of GISTs unpredictably malignant: there are no "benign" GISTs, and the most recent consensus statement proposed a classification in very low, low, intermediate and high-risk tumors based on their potential for metastases and recurrence (2, 12, 32).
The most consistent histopatological features to predict GISTs evolution are tumor size and mitotic index (32, 52). (table 1)
The ki-67 proliferative index was suggested to be a stronger predictive factor then the mitotic rate in some studies (77, 78), but inferior in other studies (79, 80). A risk score based on the sum of the tumor size and the ki-67 maximum proliferative index was proposed to stratify GISTs in two groups: one with a good outcome (risk score < 7) and one with a poor prognosis (risk score >/= 7) useful for the design of treatment protocols (4). Practically any GIST that has 6 cm or more (in greatest dimension), regardless of the proliferative index, and any GIST with a Ki-67 proliferative index >/= 5, regardless of the tumor size have a malignant behavior (fig. 4).
Other clinical and pathological prognostic factors were studied: histological type (some studies suggested a better outcome for the epithelioid GISTs (81), other studies do not support this idea (47)), cellularity (82), nuclear pleomorphism: aneuploidy is a negative prognostic factor (83, 84), CD34 is considered to be negative prognostic factor while CD44 is a good prognostic factor (5), location (gastric tumors appear to have a better outcome than intestinal GISTs) (15, 20, 85-87), tumor necrosis and hemorrhage seem to be negative prognostic features and rupture of the tumor is unfavorable because of the tumoral cells spreading, and especially because of the peritoneal seeding (5).

Figure 4

The possibility of performing a complete resection is an important positive prognostic factor and even patients with locally advanced tumors (direct extension into adjacent organs) have a overall survival similar to those with localized lesions if radical surgery can be employed. The presence of distant metastasis results in a poor outcome in GISTs.
The recent molecular studies in GIST revealed other possible prognostic factors: if first tumoral DNA studies suggested that exon 11 mutation of the KIT gene are a malignant feature (3, 52, 53) more recent evaluation find that KIT exon 11 mutations are also observed in small and low grade GISTs (18, 51).
Mutations associated with an unfavorable clinical course are the KIT exon 9 mutation that seem to define a distinct subset of GISTs with small bowel localization and an aggressive behavior (12, 47, 60, 61). Further more in the clinical practice the KIT exon 9 mutations as well as the wild-type c-kit seem to be less responsive to imatinib therapy then kit exon 11 mutations (10, 49, 65) even if all KIT mutant isoforms were equally sensitive to imatinib in vitro (65). In a recent study published by Lasota et all the majority of KIT exon 13 mutants had a spindle-cell morphology and the gastric KIT exon 13 mutant GISTs tended to be larger and more aggressive (88).
Other recent studies showed that kinase domain mutant D816v KIT and PDGFRA D842V mutation are resistant to imatinib (49, 61, 89) and therefore have a worst prognosis. There is still a subset of GISTs lacking KIT mutations, in wich gain-of function PDGFRA mutations can provide a clinical response to imatinib, and therefore the imatinib treatment should not be withheld from patients whose GISTs do not express KIT or lack KIT mutations, a molecular subclasification of GISTs being crucial to identifie patients that will not respond to imatinib (65, 66).
Further more, molecular studies identified several genes variably overexpressed in malignant behaviour GISTs, including several tyrosinekinases, MAP kinases, growth factor and cell cycle regulators, six of them having a statistical significance: CCNB1, CENP-F, FAK, HMG-2, TSG 101 and VIL 2. These results suggest that testing the expression profile of a number of genes may segregate GISTs into groups of different tumoral behavior (90).

Tumor staging in GIST
There is no universally accepted staging for GIST. The most popular classification is the one proposed by Ng et al in 1992 (91, 92) and based on a TGM system:
Tumor size:
T1 = localized and < 5 CM
T2 = localized and >/= 5 cm
T3 = contiguous organ invasion or peritoneal implants
T4 = tumor rupture
Tumor grade:
G1 = low grade
G2 = high grade
M0 = no metastasis
M1 = distant metastasis
I = T1G1M0
II = T2G1M0
III = T1-2G2M0 T3G1-2M0
IVa = T1-3G1-2M1 or residual disease after surgery
IVb = T4G1-2M0-1
The authors found that the 5 years survival in GIST is correlated with the stage as it follows:
Stage I - 75%
Stage II - 52%
Stage III - 28%
Stage IVa - 12%
Stage IVb - 7%.
An other classification was proposed by Horowitz et al in 1995 (93) based on a number of adverse factors (high grade, size larger than 5 cm, invasion or perforation and sarcomatosis): they found stages 0 or 1 vs. 3 or 4 to be a significant predictor of survival.
Based on tumor size and mitotic index, Koga et al. proposed in 1995 a classification of resected GISTs and found a high survival rate in patients with tumors smaller than 6 cm and with low mitotic index (table 2).
The molecular studies revealed other important features of GISTs, that may predict their evolution and response to treatment. Based on this findings Corless, Fletcher and Heinrich proposed in 2004 a molecular classification of GISTs (table 3).

Treatment of GIST
Treatment of primary GIST
The last consensus meeting for the management of gastro-intestinal stromal tumors established that the standard treatment of localized GIST is surgery (13). The goal of surgery is complete resection of the tumor with clear margins (preferably about 2 cm vide) (5, 6, 13, 91, 94, 95). Since all GIST's are potentially malignant, even small tumors may need to be resected, for the less than 2 cm intramural lesions laparoscopic resection being accepted (13, 96, 97). Considering that not all intramural lesions of the gastro-intestinal tract are GIST, a preoperative pathological diagnosis should be obtained.
However the preoperative biopsy is used selectively because of the risk of bleeding, tumor rupture or tumor spill and an experienced multidisciplinary team is needed if biopsy is performed, either by endoscopic ultrasound or percutaneously (6, 12, 13, 20, 36).
The intraabdominal open biopsy is discouraged because of the risk of the tumor extravasations, unless multiple metastatic lesions are encountered. For the same reasons laparoscopic surgery is usually not of choice, and adequate surgical technique is required to avoid capsule rupture and intraabdominal spillage in all surgical procedures in GIST. Therefore complete resection "en bloc", of the tumoral mass including adjacent organs adherent to the tumor is recommended (6, 13, 91, 98, 99, 100).
The importance of negative microscopic margins on the resected piece is dubious in large tumors and not been definitely demonstrated to influence survival, but positive margins may result in a higher risk of peritoneal metastatic disease. Therefore re-excision should be considered in cases of intramural tumors excised intra - lesionally that did not infiltrate the serosal surface, and margins should be negative as well within the organ from which the GIST originates, even when the tumor may involve the peritoneal serosal surface (6, 13).
Unlike adenocarcinoma, GIST rarely metastasize in the lymph nodes, and thus lymphadenectomy in not routinely performed, being warranted only for evident nodal involvement (5, 6, 13, 20).
Since GIST's tend to grow out from the tissue of origin and displace surrounding structures rather then infiltrate them, usually only a wedge resection of the stomach or segmental resection of the intestine is required (fig. 5, 6).
For difficult locations as esophagus, duodenum, or rectum, wedge resections are technically unfeasible and wide resection are demanded (fig. 7, 8).

Figure 5
Figure 6
Figure 7
Figure 8

In case of omental or mesenteric GIST's a complete "en bloc" resection of the macroscopic disease is the treatment of choice. Complete resection should be intended in localized advanced GIST's with no visible distant metastases, complex surgical resections of the tumoral mass including the tumor along with the adjacent organs adherent to it being the adequate treatment.
A reliable definition of a localized resectable disease opposed to an advanced non-metastatic disease is impossible given the diversity of size, site and extension of the lesions, the decision of resection being in the hands of surgeon.
Adjuvant chemotherapy
Even if it is demonstrated that patients with GIST have a high incidence of recurrence after surgical resection, adjuvant therapy with conventional chemotherapeutic agents is not indicated because of their lack of activity.
Adjuvant treatment with imatinib after macroscopically complete resection of the localized GIST's remains investigational, and should only be given in clinical trials (13), because it may be able to eradicate microscopic disease, but on the other hand it may also facilitate emergence of imatinib-resistant cell-clones and reduce the efficacy of the treatment of recurrent GIST.
There are few ongoing clinical trials concerning adjuvant imatinib: two in Europe: a phase III trial conducted by the EORTC soft-tissue and bone sarcoma group that randomly allocates 400 GIST patients with intermediate or high risk of disease recurrence to receive two years of imatinib mesylate or no further therapy after complete resection and a randomized phase II trial conducted by the Scandinavian Sarcoma Group in which 80 patients at high risk of recurrence or with completely resected metastatic disease are allocated to 12 or 36 months of adjuvant imatinib; the dose of both studies being 400 mg daily, and other two studies are currently running: the American College of Surgeons Oncology Group study in USA, with 380 GIST patients with tumors>/= 3 cm in diameter randomized to receive after the complete surgery either 400 mg imatinib for 1 year or placebo, and the Radiation Therapy Oncology Group study assessing neoadjuvant and adjuvant imatinib patients with resectable GIST.
While the results of these trials are expected (they will be available in a few years) for the time being adjuvant imatinib should be regarded as experimental and is not recommended as standard therapy in localized GIST (13, 15, 20).
Neoadjuvant chemotherapy with imatinib
The neoadjuvant imatinib is not recommended outside of clinical trials, as there is no current data to support it when any decrease of tumor size will not affect surgery.
For special tumor locations as esophageal or rectal GIST when functional sparing surgery is the goal, neoadjuvant imatinib treatment can be used in an attempt to achieve cytoreduction and organ preservation (13). The main difficulty in these cases is the evaluation of imatinib response, therefore a specialized multidisciplinary team of physicians is required to manage the pretreatment and asses by PET and CT scan the response, and then to perform the surgical treatment after sufficient shrinkage (between 4 to 6 month).
Regarding the follow-up after resection of primary tumor, there is no evidence of it's benefit in GIST. The most reasonable method is considered to be a systematic follow-up with CT scan: for high and intermediate risk-tumors. (>5 cm or with a mitotic index >5/50 HPF (32)) a CT scan every 3-4 month for 3 years, than every 6 month until 5 years and yearly after that; for low or very low risk tumors (<5cm and with a mitotic index <5/50 HPF (32)) a CT scan every 6 month for 5 years (13).
Treatment of advanced GIST
The last consensus meeting for the management of GISTs recommended immediate treatment with imatinib mesylate for unresectable and/or metastatic GIST. This recommendation includes all patients with metastatic disease, even those in which complete resection of the liver or peritoneal metastases is performed, because although this is technically feasible in some cases, it is not curative and their prognosis remains that of metastatic disease (13, 91, 94, 95).
Imatinib mesylate (Gleevec) is a landmark achievement in cancer therapy. It is a selective competitive inhibitor of certain tyrosine kinases, including, ABL, BCR-ABL, ARG, KIT, PDGFRA and PDGFRB (6, 12, 65, 101-105).
Developed by dr. Brian Druker, this drug is worldwide known for its effectiveness in the treatment of chronic myelogenous leukemia (CML), where inhibits the kinase activity of the BCR-ABL fusion protein (12, 15, 101, 104, 106). The studies using imatinib in CML begin in 1998 (6), and shortly after, in 1999, two important observation suggested that imatinib might be effective against GIST's: imatinib blocked the in vitro activity of both wild type kit and exon 11 mutation KIT and inhibited the growth of a GIST cell line containing a kit gene mutation (12). On these preclinical bases, in march 2000 a single patient pilot study that confirmed efficacy of imatinib mesylate in GIST begin. It was a 50 years old woman with liver metastatic GIST with exon 11 mutation who had already failed a variety of chemotherapies and who received a once-a-day dose of 400 mg of imatinib mesylate. The response evaluated using FDG-PET and CT scan revealed after only few weeks a partial response in tumor size (a decrease in size of 75% of the liver metastases), six of the 28 lesions were no longer detectable on follow-up MRI scan after 8 month of therapy, a dramatic reduction in tumor uptake of FDG in PET scan (near complete inhibition of uptake), and the tumor biopsies revealed myxoid degeneration after only 4 weeks of treatment. imatinib was well tolerated and cancer - related symptoms disappeared (107). Encouraged by these results, and with the knowledge of the experience of using imatinib in CML, several phase II and phase III studies of imatinib mesylate in GIST were than employed.
The two phase II studies developed in 2000 - 2001, one with a 400 - 600 mg dose daily and other with the highest dose feasible - 400 mg twice a day, revealed a partial response at a median follow - up of 2 years of 63% and 67% respectively and 19 % vs 18 % stable disease (108, 109). Side effects were mild to moderate, the most frequent being nausea, periorbital edema and fatigue. A few patients developed bleeding as result of the rapid tumoral necrosis induced by imatinib (6, 15, 108, 109).
Based on the results of the phase II studies the US Food and Drug Administration approved imatinib mesylate treatment for unresectable and metastatic GIST on February 1, 2002 (12). The two phase III studies of imatinib in GIST's: the North America Sarcoma intergroup study S0033 and the EORTC soft Tissue and Bone Sarcoma Group study confirmed the phase II results (110, 111). For the S0033 study that enrolled 746 patients the progression free and overall survival was not significantly different between the two arms (400 mg vs 800 mg daily): at 2 years progression - free survival rates are 50 % for the 400 mg doze vs 53% for the 800 mg doze and survival estimates are 78 % vs 73 %, with the mention that 106 patients crossed over to the higher dose after having progressive disease on the 400 mg daily doze. Among these: 7% had a partial response and 32 % stable disease with the higher dose, showing that a increased dose may offer a benefit in these cases (15, 110).
The second phase III trial (the EORTC study) randomized 946 patients to receive 400 mg imatinib daily or 400 mg imatinib twice daily. The 2 years overall survival estimates were 69% for patients treated with 400 mg and 74 % for those that started at 400 mg 400 mg twice daily. Progression free survival rates were 44 % and 52 % (p=0,26), showing a significant statistical difference (15, 111).
The different results in the two studies may have a few explanations: the EORTC study enrolled a greater number of patients, thus resulting in detecting statistical significant differences.
The location of KIT mutation was not analyzed in neither of the two studies, so that a different genetic composition of patients enrolled can lead to the discrepancy in the results (it is possible that exon 11 mutation, the most sensitive to imatinib, was more frequent in the EORTC study).
Regarding the safety of imatinib administration, the phase III study of EORTC reported the following early toxicity results: most side-effects were mild to moderate (grade 1 or 2). The most frequently encountered side-effects were: anemia (88%), edema (67%), fatigue (60%), nausea (40%), neutropenia (32%) and skin rush (24%). One patient died of drug related neutropenic sepsis. The conclusion was that imatinib was safe and generally well tolerated at doses up to 800 mg daily (15, 112).
Based on the results of the trials regarding imatinib mesylate treatment in unresectable and/or metastatic GIST, the ESMO Consensus Meeting in 2004 established that the currently recommended dose for the first - line treatment in advanced GIST is 400 mg/day, with the mention that longer follow-up of the treatment is needed (13).
A recent randomized phase III trial conducted by the French Sarcoma Group showed that interruption of imatinib after 1 year is associated with a high risk of relapse, even if the disease is in complete remission, and not all patients (although most of them), respond to reintroduction of the drug (113). Therefore imatinib mesylate treatment needs to be given until the progression of the disease, intolerance or patient refusal (13).
In a recent article, Fiorentini et al. get to the conclusion that imatinib mesylate is superior to intraarterial hepatic chemotherapy in liver metastases from gastrointestinal stromal tumors (114).
The imaging follow-up in advanced tumors treated with imatinib has the goal of assessing the tumor response.
FDG PET is the most sensitive method in detecting early tumor response (67, 115), but the high cost is limiting it's use.
For the present time the imaging modality of choice in response evaluation is the CT scan, unless a very short - time follow-up is needed (in terms of weeks to decide a surgical aproach in "marginally resectable" tumors), (13) in which PET scan is necessary.
For the liver metastasis MRI is an possible option, and the role of ultrasound is currently under investigation.
Imatinib treatment induced in many cases a partial remission or at least provides stable disease, but it can be beneficial also in a subset of patients that undergo an initial increase in tumor volume, because during the early post-treatment phase (within the first 6 months) tumors can suffer intratumoral hemorrhage, edema or myxoid degeneration which are responsible for the increase in size, and that must be distinguished from tumor progression. Use of CT scan to evaluate the reduction in tumor density by CT attenuation coefficient (HU), or MRI, and/or decreased glucose uptake at PET scan can demonstrate an early response in tumor size appears later in the therapy, particulary in hepatic metastases (115-118).
The last Consensus Meeting for the Management of GIST's established that 3 parameters are predictors of tumor control by imatinib: 1 - the clinical improvement under imatinib treatment; 2 - CT scan response and HU reduction and 3 - the decrease of FDG uptake on PET scan (13).
Once the tumors have responded to imatinib the imaging follow up by CT scan has to be done every 3-4 month to detect recurrence (119, 120). If CT findings are inconclusive or inconsistent with the patient's clinical symptoms, PET scan can be used for further evaluation (13).
The recurrence in GIST treated with imatinib includes new lesion at the site of surgical resection, a new metastasis or increasing size of the preexisting lesions. The development of an intramural module and/or an increase in density on the back ground of a hypodense lesion under imatinib therapy can also mean a recurrence in GIST.
For the patient who exhibit response to imatinib surgery can be an option if surgical removement of all visible tumors is possible. This procedure is considered for the moment to be experimental, and should be performed when the maximal response to imatinib has been reached (between 4-12 month after the onset of imatinib therapy), by an experienced team. Metastases can be removed by resection (fig. 9) or experimental destruction procedures as radiofrequency ablation.

Figure 9

Imatinib treatment must be continued even after complete resection, because of the risk of the recurrence (6, 13, 121).
The patients who exhibit tumor progression under imatinib therapy can be divided in two group: patients with primary resistance that have tumor progression within the first 6 month of imatinib therapy and patients with secondary resistance, that occurs after 6 month of imatinib treatment (13).
Recent studies suggest that imatinib resistance has four different mechanisms: 1 - acquisition of a secondary point mutation in KIT or PDGFRA with consecutive drug resistance; 2 - kinase over expression due to genomic amplification of KIT; 3 - activation of an alternate receptor tyrosinekinase with loss of kit oncoprotein expression; 4 - functional resistance in tumors expressing kinases that are imatinib sensitive in vitro - see the wild - type kit or exon 9 mutation KIT (12).
Patients with primary resistance have tumors that exhibit wild - type KIT, exon 9 mutation or mutated PDGFR alpha with D842V mutation (12, 49, 65, 122). They have generally multifocal disease.
The Consensus Meeting for the Management of GIST in 2004 established that secondary resistance occurs in two different patterns:
1. Partial resistance: one or a limited number of metastasis showing a nodule within a mass and/or an increase in size with increased FDG uptake on PET scan, while other sites remain controlled by imatinib (13).
In this situation, local treatment of the metastasis, along, with increased dose of imatinib or alternative experimental targeted therapy can be considered. A multidisciplinary team is needed to perform the treatment, that may include surgical resection of the liver and/or peritoneal metastasis, radiofrequency ablation, hepatic artery embolization or intraperitoneal chemo-therapy (6, 94, 123, 124).
2. Multifocal resistance: the role of the local treatment is not demonstrated in this situation. Increasing doze of imatinib (800 mg/day) or an alternative experimental targeted therapy (such as SU 11248 = sunatinib) is the option for the patients in good clinical condition (13, 125).
Sunatinib (SU 11248) is a new tyrosine kinase inhibitor currently in clinical trials which yielded a 7% response rate and 58% prolonged stable disease in a series of 92 imatinib resistant GIST patients (20, 126-128). Recently, Pantaleo et al. reported 2 cases of patients with metastatic GISTs who underwent surgery after second-line chemotherapy with sunitinib, both of them having durable stable disease on sunitinib, but developing adverse reactions to chemotherapy (one with chronic bleeding and other with chronic heart toxicity), the authors suggesting that surgery could represent a reasonable choice for advanced GISTs if the risk of surgery-related death is not too high (129).
In conclusion, the role of surgery is primordial in GIST, being indicated in all the cases in which the tumors are resectable, the targeted chemotherapy with imatinib mesylate being reserved for the advanced disease (un-resectable or metastatic GISTs).
Further progress in the development of new kinase - targeted inhibitors is expected, and combinations of novel molecular targeted drugs are allready being studied - for example perifosine (a new alkylphospholipid with antiproliferative properties attributed to protein kinase B inhibition) in combination with imatinib (130, 131).
Understanding the pathogenic pathways of GIST can open the way for understanding more about other human cancers and for the development of new molecules with targeted action in different types of neoplasias.

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