Gastrointestinal Stromal Tumors Research Proposal

Length: 10 pages Sources: 50 Subject: Genetics Type: Research Proposal Paper: #59820068 Related Topics: Genetics, Muscular System, Molecular, Stem Cell
Excerpt from Research Proposal :


Liegl-Atzwanger, Fletcher and Fletcher (2010) pointed out that the exact incidences of gastrointestinal stromal tumors in the United States and Europe is not easy to determine. This is attributed to the fact that GISTs got proper recognition as well as diagnosis from the late 1990s.Studies carried out in Iceland ( Tryggvason et al.,2005), Sweden (Nilsson et al.,2005), as well as Holland (Goettsch,2004) have indicated that close to 11,14.5 and 12.7 cases per million people per year respectively.Incidences if GISTs have been shown to be higher as a result of the fact that most patients live with it for several years and it gets detected only during gastrectomy or autopsy all of which are usually performed for other reasond. A study by Agaimy et al.,(2007) which was performed consecutively on autopsies indicated that small GISTs having between 1-10 mm in about 22.5% of the individuals aged above 50 years.These small GISTs were indicated as being immunoreactive for KIT and Other studies reported similar findings (Agaimy et al.,2008;Kawanowa et al.,2006;Corless et al.,2002). The findings suggest that the minute GISTs never progress quite often into large tumors.This is despite the fact that KIT is present or there are PDGFRA mutations. During the diagnosis, most patients having GIST are shown to be in the age group 40-80 years with a median age of about 60 years (Liegl-Atzwanger, Fletcher and Fletcher,2010). GISTs have been shown to bear no gender predilection (Miettinen, Sobin, Lasota, 2005a).In rare cases GISTs are discovered in young adults and children. It is worth pointing out that Pediatric GISTs are considered a completely separate clinicopathologic situation and has been indicated to occur in the second decade (Prakash,2005; Miettinen, Sobin, Lasota, 2005b;Janeway et al.,2007).It has been indicated that most cases of GISTs are rather sporadic with a clear description of families possessing KIT mutations as well as GISTs that are germ-line in nature (Beghini et al.,2001;Isozaki et al.,2000;Kang et al.,2007;Maeyama et al.,2001;Nishida et al.,1998;O'Riani et al.,2005;Kleinbaum et al.,2008;Pasini et al.,2008;Li et al.,2005).The development of GISTs can be associated with the development of certain hereditary conditions such as Carney's triad (Carney,1999, Carney and Stratakis,2002).Carney's dyad (Pasini et al.,2008) and neurofibromatosis type I (Anderson et al.,2005;Maetens et al.,2006;Miettinen et al.,2006).GISTs incidences prior to the year 2000 is never known. At present however, there are about fifteen cases to a million in the United States as well as approximately eleven cases to a million in Sweden and Iceland (Northern European states). The prevalence rate is ten to twenty cases up to a million (Edmonson et al.,2002;Fletcher et al.,2002).GISTs are the most common mesenchymal tumors that occur in the digestive system with an 80% rate (Liegl-Atzwanger, Fletcher and Fletcher,2010).This represents between 3 to 5% percent of al the soft tissue sarcomas and about 3% of gastrointestinal tumors. GISTs can develop in almost any part of the digestive system. The most frequent sites of localization being the stomach (about 60%) and the small intestine (between 20 and 30%).In the small intestine, it mostly affects the ileum and jejunum. Localizations l such as the large intestine (about 5%) as well as the esophagus is in about just 2 to 5% of the cases. The stromal tumors that are localized in places that lie outside the gastrointestinal tract like the pancreas and bladder are considered to be exceptional. The most cases of metastases have been established to be due to omental, mesenteric and retroperitoneal localizations (Mazur and Clark,1983; Miettinen, Virolainen, Maarit Sarlomo, 1995). Most of the GISTs undergo development up to the 5th and 6th decade and are not usually diagnosed in patients who are younger than forty years. GISTs rarely occur in children and the occurrence rate is less than one percent in the 2nd decade. The predilection for the females, variants of epithelioid and gastric localization is the dominant morphological aspects (Hirota et al.,1998;Huizinga et al.,1995). There has never been any demonstration of sex related predilection. Some data however seems to indicate that there is a predominance of GISTs in patients who are male.


Fulop et al. (2009) conducted a review on the morphology, diagnosis as well as the


Hirota and Isozaki (2006) carried out a study of the pathology of Gastrointestinal stromal tumors and pointed out that they are the most common types of mesenchymal tumors that affect the gastrointestinal tract. In their work, they pointed out that initially the term GISTs had a descriptive appeal to it.They pointed out that the term was originally coined by Mazur and Clark in 1983 in order to describe the abdominal tumors.These tumors were never carcinomas and they never presented any characteristics of nervous cell tumors or smooth muscles (Mazur and Clark,1983) pointed out that most cases of GIST occur in a sporadic fashion and most of the cases adopt a solitary lesions presentation. These cases have an exophytic growth which is predominant along the gastrointestinal tract and thereby protruding dominantly into the abdominal cavity. In cases where the tumors are small, the mucous membrane usually remains intact. In large cases in which the tumor is also aggressive, there is also certainty that ulceration would occur. In the case of small tumors however, the mucosa's muscle layer appears to coalesce with the muscular layer. In some cases however, it compresses itself against the muscular layer. It is however, delimited from the muscular layer by a relatively thicker band of collagen (Miettinen, Sarlomo-ikala and Sobin,2001).In certain cases, the tumor assumes a centered position within its own muscular layer, a position which determines whether it would protrude towards the outer parts/surfaces of the victim's intestinal walls or cause an invasion of the mesentery. The invasion of the organs which are in the vicinity can be identified in almost a third of all cases (Fulop et al., 2009). Metastases are common in GISTs and are reported in about half of the patients. The organi with the most cases of metastases is the liver (about 65%) and is followed closely by the peritoneum (about 21%). Cases of metastases in the lungs, lymph nodes and bones are considered to be rare occurrences.

The tumors are usually delimited quite well, on-encapsulated, whitish and firm in their consistency.

Smaller lesions that have a homogenous sectional surface as well as larger ones that present zones having neclorisis as well hemorrhaging cysts are common. The cellularity of the cysts can range from moderate to high. The cysts can be divided into epithelioid, spindle cell, signet ring, oncocyctic variants, pleomorphic cells having myxoid stroma.

GISTs having spindle cells

Fulop et al. (2009) pointed out that 70% of tumors in existence are mainly of spindle cell type. In this form, the cells are usually uniform, densely packed and elongated as shown in the image below.

Figure 1:GISTs having features of a spindle cell as well as possessing a uniform pattern (Source: Fulop et al. (2009)).

This type of tumor may appear in various patterns such as storiform, herringbone or pallisading pattern. The nuclei of this form of Cyst are monomorphous, highly flattened and having blunt ends. They may also be cigar or bullet shaped as shown in Figure 2.

Figures 2: GISTs having spindle cell features but with nuclei having blunt ends (Fulop et al.,2009).

Fulop et al. (2009) pointed out that nuclear polymorphism is never a characteristic of GISTs.In these cysts, the cytoplasm is kind of sparse, are basophilic are not usually eosinophilic. They however in certain cases have vacuoles that juxtanuclear and PAS positive. These tumors have been noted to be able to simulate the tumors having natural sheath or the smooth muscles tumors. This is usually the case whenever palisade-type of nuclei is achieved as shown in Figure 3.

Figure 3: GISTs that have foci of the spindle cell palisades.

Miettinen et al.,(2003) and Miettinen et al.,(2006) pointed out that cases of rich vascularization coupled with hemorrhage, myxoid degeneration, hyanilization as well as calcified zones. This is more observed in large tumors.

The appearance of the eosinophilic collagen globules (skeinoid fibers) is determined by the appearance of excessive hyanilization. These features are definite in the cases of GISTs in the small intestine.These aspects of the tumors have been noted to the tumors that have a lower level of malignancy and which in turn is associated with prognosis which is better.

GISTs having epithelioid cells

Miettinen et al.,(2005) described a pronosis for the GISTs having epitheliod cells and said that their microscopic forms can be observed in gastric tumors that shown polugonal or round cells and possessing eccentric or round nuclei with vacuolization which is perinuclear. The tumors that have small cells that are organized into nests and/or exhibiting alveolar disposition appear to metastasize more often. These cells have been shown to have an abundance of cytoplasm that are clear, eosinophilic or amphophilic. The nuclei have been shown to be well rounded with a rather small nucleoli. Fulop et al. (2009) pointed out that giant cells with scattered nuclei or cells whose nuclei are bizarre can be presented as shown in figure…

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About 50% of the GISTs exhibit a loss of gene off the arm of chromosome 22. This discovery is associated with the progression of the malignant GIST (Fukasawa et al.,2000;Bergmann et al.,1998;Kim et al., 2000;Lasota et al.,2007). There are however some losses that are less frequent on the chromosomes 9q,17q,1p and 11p.Gains are however noted on chromosomes 17q and 8q all of which have a strong association with malignant behavior (El-Rifai et al.,2000;Schurr et al.,2006).

Clinical features

Extant literature has been dedicated to the study of the clinical features of GISTs.GISTs are mentioned by Liegl-Atzwanger, Fletcher and Fletcher (2010) to occur in almost every part of the GI tract.They are however more common in the stomach regions ( about 60%), ileum and jejunum (close to 30%), colorectum (about 4%) and duodenum (about 5%).GISTs are rarely seen in the appendix and esophagus (Miettinen et al.,2006;Miettinen, Sobin and Lasota,2005;DeMatteo eat al.,2000). Tumors that lack any form of association with the wall of the bowel are given special name- extragastrointestinal stromal sarcomas are noted to occur in the mesentery, omentum and retroperitoneum (Miettinen et al.,1999;Reith et al.,2000). The clinical symptoms that are associated with GIST are abdominal pain, dysphagia, obstruction, fatigue and satiety.It has been noted that patients may be presented with chronic bleeding to from their GI (Causes anemia). The patient may also present acute bleeding to GI ( as a consequence of the erosion via the gastric or the bowel mucosa). There could also be a rupture into the patient's abdominal cavity thus causing a life-threatening condition called intraperitoneal hemorrhage. Nilsson et al. (2005) indicated that a population-based research indicated that close to seventy percent of GISTs were related to clinical symptoms while twenty percent were not. 10% were detected at the time of autopsies.

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