الفهرس 
COVEROnly 14 pages are availabe for public view
 |  | from | 141 |  |  |
| | | from | 141 | | |
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, Neoplastic GIST cells seem to arise from a common precursor cell, which gives rise to the interstitial cells of Cajal in the normal myenteric plexus. GISTs can arise anywhere along the gastrointestinal tract but are most common in the stomach and small intestine. GISTs can also originate in the mesentery and omentum.
The term GIST was introduced by Mazur and Clark in 1983 while in 1998 it has become clear that the actual cell of origin of GISTs is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal .
On gross examination GIST is a well circumscribed, fleshy, pink or tan-white mass. Large tumors frequently show hemorrhage, necrosis and cystic degeneration. Microscopically, GISTs can be divided into three different histologic subgroups. Spindle cell GISTs (70%) ,Epithelioid GISTs (20%) The final group shows mixed spindle and epithelioid cells (10%). The frequency of these histological types varies according to location.
GISTs pathogenesis relies on mutations in KIT or PDGFRA receptor tyrosine kinase proteins, mutations cause functional changes in KIT and PDGFRA proteins, usually leading to ligand-independent dimerization and constitutional activation, leading to formation of the tumor.
The diagnosis of GISTs is mainly based on clinical and histological findings, but immunohistochemical staining is needed to confirm diagnosis.
The most important marker for GISTs which is the key feature is positivity for the KIT (CD117) receptor tyrosine kinase, observed in more than 95% of GISTs. Other markers include CD34 is positive in 60-80% of GISTs Protein kinase C (PKC)-theta staining is positive in approximately 90% of GISTs. H-caldesmon is positive in 60-80% of GISTs, which may be helpful in the diagnosis of c-kit negative GISTs. Smooth muscle actin is positive in 30-40% of GISTs S-100 and desmin is positive in 5% and 1-2% of GISTs, respectively recently developed antibody against DOG1 (discovered on GIST) was reported to be superior in sensitivity and specificity to c-kit and CD34. However, c-kit negative GISTs express DOG1 in only 36% of cases.
Histological differential diagnosis includes smooth muscle tumors, nerve sheath tumors, desmoids, inflammatory myofibroblastic tumors, inflammatory fibroid polyps, and undifferentiated sarcomas.
GISTs may be asymptomatic, or may be presented clinically by abdominal discomfort, pain, bleeding into the intestinal tract and abdominal mass. It may be presented as an emergency by intestinal obstruction or acute abdomen due to tumor rupture. Approximately 20% to 25% of gastric and 40% to 50% of small intestinal GISTs are clinically malignant and may be presented with metastases.
The initial diagnosis is generally made by endoscopy, capsule endoscopy, endoscopic ultrasound , pelvi-abdominal ultrasound , barium studies, pelvi-abdominal CT, MRI and PET scan.It should be confirmed by pathologic histological findings after resection.
Surgery is The standard of care and the only potentially curative therapy for patients with primary, resectable , localized GIST where The goal of the surgery should be a macroscopically complete resection with an intact pseudo-capsule and a negative microscopic margin (R0 resection).
Laparoscopic resection should be reserved for small, favorably located gastric GISTs while endoscopic therapies { snare electrosection, endoloop , Endoscopic mucosal resection (EMR) and Endoscopic submucosal dissection (ESD)} are safe method for treatment of premalignant lesions and early malignant gastrointestinal epithelial and subepithelial lesions yielding high cure rates with low recurrence.
The goals of pharmacotherapy (including Imatinib mesylate and Sunitinib malate) are to induce remission, reduce morbidity, and prevent complications. It’s used in unresectable tumors, resectable tumors with gross residual disease or after complete resection in high risk tumors (size > 5 cm, positive margins, mitosis >1/10 HPF, tumor necrosis, rupture or hemorrhage).
imatinib 400 mg daily is the standard of care In locally advanced, inoperable and metastatic GIST even for patients who have undergone complete resection of metastatic disease. and imatinib 800 mg daily is recommended for patients whose GIST harbors KIT exon 9 mutations while Sunitinib is the standard treatment for patients who have progressed on or are intolerant to imatinib .
Prognostic factors influencing survival and tumor recurrence depend on patient characteristics (age and sex), tumor gross (size, location, and resection margin), and microscopic features (mitotic index, cellular markers, presence of necrosis or ulceration).
Outcomes in patients with GISTs are highly dependent on the clinical presentation and the histopathological features of the tumor. The overall 5-year survival rate ranges from 28-60%. This can be stratified for patients presenting with localized primary disease and those presenting with metastatic or recurrent disease. The median survival rate in the former group is 5 years, while the median survival rate in the latter group is approximately 10-20 months. Larger GISTs are associated with complications such as GI hemorrhage, GI obstruction, and bowel perforation.
Further researches are necessary for safer drugs and possibility of prevention of mutation in benign Gists.