Gastrointestinal stromal tumors ( GISTs ) are the most common mesencalal neoplasms in the gastrointestinal tract. GIST appears in the interstitial cells of the Cajal smooth muscle stem cells, or similar cells. They were defined as tumors whose behavior was driven by mutations in the KIT gene (85%), PDGFRA (10%), or BRAF kinase (rare) genes. 95% GIST stained positive for KIT (CD117). Most (66%) occur in the stomach and Gist's stomach has a lower malignant potential than tumors found elsewhere in the gastrointestinal tract.
Video Gastrointestinal stromal tumor
Classification
GIST was introduced as a diagnostic term in 1983. Until the late 1990s, many non-epithelial gastrointestinal tumors were called "gastrointestinal stromal tumors". Histopathologists can not specifically distinguish between the species we now know as not molecularly. Furthermore, CD34, and then CD117 are identified as markers that can differentiate between different types. Moreover, in the absence of specialized therapy, diagnostic categorization has only a limited effect on prognosis and therapy.
The understanding of GIST biology changes significantly with the identification of GIST molecular basis, especially c-KIT. Historically, the literature review before the GIST molecular definition, and for a short time thereafter, confirmed that 70-80% of GIST is benign. The identification of molecular basis for GIST led to the exclusion of many tumors that have been considered as GIST before, as well as the incorporation of large numbers of tumors that have been labeled as other types of sarcomas and undifferentiated carcinomas. For example, some previous diagnoses of gastric and small intestine leiomyosarcomas (malignant smooth muscle tumors) will be reclassified as GIST on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant potential, and no GIST tumors can be definitively classified as "benign". Therefore, all GISTs are eligible for staging the cancer in AJCC (edition 7)/UICC. However, different GISTs have different risk assessments of their tendency to recur or metastasize, depending on their origin site, size, and number of mitotic figures.
Due to the change in definition, the path of pre-2000 clinical care is largely uninformative in the current era.
Maps Gastrointestinal stromal tumor
Signs and symptoms
GIST may present with difficulty swallowing, gastrointestinal bleeding, or metastasis (especially in the liver). Intestinal obstruction is rare, due to growth patterns outside the tumor. Often, there is a history of uncertain abdominal pain or discomfort, and the tumor becomes rather large at the time the diagnosis is made.
Pathophysiology
GIST is a tumor of connective tissue, which is sarcoma; unlike most gastrointestinal tumors, they are nonepithelial. Approximately 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally benign, especially when the rate of cell division is slow, but large tumors spread to the liver, omentum and peritoneal cavities. They rarely occur in other abdominal organs.
GIST is thought to have originated from the Cajal interstitial (ICC) cell, which is usually part of the gut ot autonomic nervous system. They serve pacemaker functions in controlling motility.
Genetics
Most GISTs are sporadic. Less than 5% occur as part of a family or idiopathic multithullary hereditary syndrome. These include, in the sequence of frequencies, Recklinghausen neurofibromatosis (NF-1), Carney triad (GIST stomach, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations in c-Kit/PDGFRA, and Carney-Stratakis Syndrome. Carney-Stratakis syndrome is a measure of hereditary Gist and paraganglioma, caused by germline mutations in the pathway of mitochondrial tumor suppressor genes involving succinate dehydrogenase (SDH) SDHD subunits, SDHC and SDHB. Triad Carney does not feature SDH mutations.
mutation c-KIT
Approximately 85% of GIST is associated with an abnormal c-KIT path. c-KIT is a gene that encodes transmembrane receptors for growth factors called stem cell factors ( scf ). The most common abnormal c-KIT pathway occurs from the gene mutation itself; a smaller subset of GIT-related KIT is associated with the constitutive activity of the enzymatic pathway KIT , found by immunoblotting. The product of c-KIT/CD117 is expressed on ICC and a large number of other cells, especially bone marrow cells, mast cells, melanocytes and several others. However, in the intestine, a positive bulk dye for CD117 is likely to become GIST, arising from ICC cells.
The c-KIT molecule consists of a long extracellular domain, a transmembrane segment, and an intracellular portion. Mutations generally occur in DNA that encodes an intracellular part (exon 11), which acts as a tyrosine kinase to activate another enzyme. Mutations make the C-KITfunction independent of activation by scf , leading to high levels of cell division and possibly genomic instability. Additional mutations are likely to be "necessary" for cells with a mutated c-KIT mutation into GIST, but a mutation of c-KIT may be the first step of this process..
Mutations in exons 11, 9 and rarely 13 and 17 genes c-KIT are known to occur at GIST. The tyrosine kinase function of c-KIT is important in medical therapy for GIST, as described below.
- The KIT-D816V mutation point at c-KIT exon 17 is responsible for resistance to targeted therapeutic drugs such as imatinib mesylate, tyrosine kinase inhibitor.
- KIT-p.D419del (exon 8) - A subset of gastrointestinal stromal tumors previously considered a wild-type tumor carrying a somatic activation mutation in KIT exon 8 (p.D419del).
PDGFRA mutation
Most GIST cells with wildtype (ie not mutated) c-kit instead have mutations in other genes, PDGFR-? (alpha receptor growth factor of platelet alpha), which is a related tyrosine kinase. Mutations in c-kit and PDGFrA are mutually exclusive [4] [5].
Wild type Tumors
Less number of GIST does not seem to be associated with c-kit or PDGFR-? abnormalities. Approximately 10-15% of gastrointestinal stromal tumors (GISTs) carry a wild-type sequence at all KIT hot spots and platelet-derived alpha receptor factor (PDGFRA) (wt-GISTs). This tumor is currently defined with no mutations in exons 9, 11, 13, and 17 of the KIT gene and 12, 14 and 18 exons of the PDGFRA gene.
Diagnosis
CT scans are often performed (see section radiology ).
Definitive diagnosis is made by biopsy, which can be obtained by endoscopy, percutaneous with CT or ultrasound guidance or at the time of surgery. The biopsy sample will be investigated under a microscope by a pathologist. Pathologists examine histopathology to identify GIST characteristics (spindle cells in 70-80%, epithelial aspect at 20-30%). Smaller tumors can usually be confined to the muscular layer of propria from the intestinal wall. The big grows, especially out, from the intestinal wall to the point where they exceed the blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the intestinal lumen.
When GIST is suspected - as opposed to other causes for similar tumors - pathologists may use immunohistochemistry (specific antibodies that color the CD117 molecule [also known as c-kit ] - see below). 95% of all GISTs are CD117-positive (other markers may include CD34, DOG-1, desmin, and vimentin). Other cells that exhibit CD117 positivity are mast cells.
If the CD117 stain is negative and suspicion remains that the tumor is GIST, newer antibodies DOG-1 (found in GIST-1) may be used. Also the Kit and PDGFRA sequencing can be used to prove the diagnosis.
Imaging
The purpose of radiological imaging is to find the lesion, evaluate the signs of invasion and detect metastasis. The features of GIST vary depending on the size of the tumor and the organ of origin. The diameter can range from a few millimeters to more than 30 cm. Larger tumors usually cause symptoms that are different from those found inadvertently that tend to be smaller and have a better prognosis. Large tumors tend to exhibit malignant behavior but small GIST may also exhibit clinically aggressive behavior.
Plain radiography is not very helpful in evaluating GIST. If the abnormality is seen, it will be an indirect sign because of the effect of tumor mass on adjacent organs. In the abdominal x-ray, GIST of the stomach may appear as a radiopaque mass that changes the shape of the air shadow of the stomach. GIST intestines may shift the intestinal loops and larger tumors may block the intestine and the film will exhibit obstructive patterns. If there is a cavity, plain radiography will show a collection of air inside the tumor. Liming is an unusual feature of GIST but if there can be seen on a regular movie.
Barium fluoroscopic and CT examinations are usually used to evaluate patients with stomach complaints. Barium swallow images show abnormalities in 80% of GIST cases. However, some GIST may lie entirely outside the intestinal lumen and will not be rewarded by swallowing barium. Even in cases where abnormal barium swallowing, MRI or CT scan should follow because it is impossible to evaluate the abdominal cavity and other abdominal organs by swallowing barium alone. In CT scans, abnormalities can be seen in 87% of patients and should be done with oral and intravenous contrast. Among the imaging studies, MRI has the best tissue contrast, which helps identify the mass in the gastrointestinal tract (intramural mass). Intravenous contrast material is required to evaluate the vascularization of the lesion.
The preferred imaging modalities in GIST evaluation are CT and MRI, and, in certain situations, ultrasound endoscopy. The benefits of CT include its ability to show evidence of invasion of nearby organs, ascites, and metastases. The ability of MRI to produce images in various fields is helpful in determining the gut as the organ of origin (which is difficult when the tumor is very large), facilitating the diagnosis.
Small GIST
Because GIST emerges from the lining of the intestine called muscularis propria (deeper into the mucosa and submucosal from the luminal perspective), small GIST imaging usually suggests submucous processes or masses within the intestinal wall. In a swallow barium study, GIST is most commonly present with fine borders forming a right or blunted corner with an intestinal wall nearby, as seen with other intramural masses. The surface of the mucosa is usually intact except for the ulcerated area, which is generally present in 50% of GIST. Ulceration filled with barium that causes bull's eye or target lesion. Instead of improved CT, a small GIST is seen as a smooth, sharp intramural mass defined by a homogeneous attenuation.
Large GIST
When the tumor grows, it can occur outside the intestine (eco-growth) and/or in the intestine (intraluminal growth), but they most often grow exsofit so most of the tumor project goes into the abdominal cavity. If the tumor exceeds its blood supply, it can necrose internally, creating a central fluid-filled cavity with bleeding and cavity that can ultimately slit and communicate into the intestinal lumen. In this case, barium swallow may indicate the level of air, air fluid or accumulation of oral contrast media in this area. Mucosal ulceration may also occur. In contrast, enhanced CT images, large GIST appear as heterogeneous masses due to the area of ​​living tumor cells surrounding bleeding, necrosis or cysts, which are radiographically seen as peripheral enhancement patterns with low damping centers. In the MRI study, the rate of necrosis and bleeding affects the signal intensity pattern. The area of ​​bleeding inside the tumor will vary signal intensity depending on how long ago bleeding occurred. The solid part of the tumor is usually the low signal intensity in the T1-weighted image, is the high signal intensity in the T2-weighted image and improves after gadolinium administration. The intensity-signal threshold is present when there is gas within the necrotic tumor area.
Malignancy features
Malignancy is characterized by local invasion and metastasis, usually to the liver, omentum and peritoneum. However, cases of metastasis to bone, pleura, lung and retroperitoneum have been seen. In contrast to gastric adenocarcinoma or gastric lymphoma of the small intestine, malignant lymphadenopathy (swollen lymph nodes) is rare (& lt; 10%) and thus imaging usually indicates the absence of enlarged lymph nodes. If metastasis is absent, other radiological features indicating malignancy include: size (& gt; 5 cm), heterogeneous increase after contrast and ulceration. Also, malignant behavior (in contrast to malignant potential at lower levels) is less commonly seen in gastric tumors, with a benign ratio of benign behavior 3-5: 1. Even if a malignant radiographic image is present, these findings may also represent other tumors and a definitive diagnosis should be made immunochemical.
Management
In adult traceable GIST, if feasible anatomically and physiologically, surgery is the treatment of primary choice. Surgery can be potentially curative, but waiting with caution can be considered on small tumors in carefully selected situations. Post surgical adjuvant treatment may be recommended. Lymph node metastasis is rare, and routine lymph node removal is usually unnecessary. Laparoscopic surgery, minimally invasive abdominal surgery using specialized telescopes and instruments, has proven effective for removing this tumor without the need for a large incision. Clinical problems of appropriate surgical indications for tumor size are controversial. Proper laparoscopic surgery decision is influenced by tumor size, location, and growth pattern.
Radiotherapy has not been historically effective for GIST and GIST does not respond to most chemotherapy drugs, with a response of less than 5%. However, three drugs have been identified for clinical benefit in GIST: imatinib, sunitinib, and regorafenib.
Imatinib (Glivec/Gleevec), an oral drug originally marketed for chronic myelogenous leukemia based on bcr-abl inhibition, also inhibits the mutations of tyrosine kinase c-kit and PDGFRA mutations other than D842V, is useful in treating GIST in some situations. Imatinib has been used in selected neoadjuvant settings. In adjuvant care settings, the majority of GIST tumors are cured by surgery, and do not require adjuvant therapy. The exception to this is where the position of the tumor anatomy means that surgery is technically difficult or complex. For example, GIST rectal often requires radical surgery to achieve complete resection, which involves abdominoperineal resection and a permanent stoma. In this situation, the use of neoadjuvant imatinib can significantly reduce tumor size and mitotic activity, and allows less radical sphincter preservation surgery.
Most GIST tumors have a high risk of recurrence as predicted by a number of stratified risk stratification schemes that are validated, and may be considered for adjuvant therapy. Selection criteria that support the decision for possible use of imatinib in this arrangement include risk assessment based on pathological factors such as tumor size, mitotic level, and location can be used to predict risk of recurrence in GIST patients. Tumor & lt; 2 cm with mitosis rate & lt; 5/50 HPF has been shown to have a lower recurrence risk than larger or more aggressive tumors. After GIST surgical resection, adjuvant treatment with imatinib reduces the risk of recurrence of disease in high-risk groups. In a high-risk adjuvant situation selected, imatinib is recommended for 3 years.
Imatinib is approved for GIST metastasis and can not be operated by the US FDA, February 1, 2002. The survival of two years of patients with advanced disease has increased to 75-80% after imatinib treatment.
If resistance to imatinib is found, some tyrosine kinase inhibitor sunitinib (marketed as Sutent) may be considered.
The effectiveness of imatinib and sunitinib depends on the genotype. cKIT- and PDGFRA-negative GIST tumor mutations are usually resistant to treatment with imatinib such as the GIST-1-associated wild-type neurofibromatosis. The specific subtypes of the PDGFRA mutation, D842V, are also insensitive to imatinib.
Regorafenib (Stivarga) is approved by the FDA in 2013 for advanced GIST which can not be surgically removed and no longer responds to imatinib (Gleevec) and sunitinib (Sutent).
Epidemiology
GIST occurs on 10-20 per one million people. The actual incidence may be higher, because new laboratory methods are much more sensitive in diagnosing GIST. The estimated incidence of GIST in the United States is about 5000 cases per year. This makes GIST the most common form of sarcoma, which is more than 70 types of cancer.
The majority of GIST is present at the age of 50-70 years. In most age spectrum, GIST incidence is similar in men and women.
Adult GIST is rare before the age of 40 years. DENTAL child is considered biologically different. Unlike GIST at other ages, pediatric GIST is more common in young women and women. They appear to be less oncogenic to activate tyrosine kinase mutations in both KIT and PDGFRA. GIST Pediatric is treated differently than adult GIST. Although a generally accepted definition of pediatric GIST is a tumor diagnosed at the age of 18 years or younger, a "pediatric-type" GIST can be seen in adults, which affects risk assessment, the role of lymph node resection, and treatment options.
References
Source
- de Silva CM, Reid R (2003). "Gastrointestinal stromal tumor (GIST): C-kit mutation, CD117 expression, differential diagnosis and targeted cancer therapy with Imatinib" (PDF) . Pathol Oncol Res . 9 (1): 13-9. doi: 10.1007/BF03033708. PMID 12704441.
- Kitamura Y, Hirota S, Nishida T (Apr 2003). "Gastrointestinal stromal tumors (GIST): a model for molecular-based diagnosis and treatment of solid tumors". Cancer Sci . 94 (4): 315-20. doi: 10.1111/j.1349-7006.2003.tb01439.x. PMIDÃ, 12824897. Ã,
External links
- GIST U.K Support
- Surgical Questions at GIST ESUN (August 15, 2006)
- SPAEN (EuroNet Patient Sarcoma) - European Network of Sarcoma, GIST and the Desmoid Patients Advocacy Group
- GIST International Support
- GIST International Group's Life Raft Group Advocacy
- American Cancer Society Patient Guide for GIST tumors.
- Cancer.Net: Gastrointestinal Stroma Tumors
Source of the article : Wikipedia
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