Epidemiology and clinical characteristics of gastrointestinal stromal tumors

Epidemiology

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.

Pathology

Fulop et al. (2009) conducted a review on the morphology, diagnosis as well as the management of gastrointestinal stromal tumors. 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 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 4 below.

Figure 4:GISTs having epitheliod features.

Genetics

According to Fulop et at.,(2009),molecular genetics as well as histogenesis GISTs represents a unique and a special group of gastro-intestinal tumors which originates from the interstitial Cajal cells (ICC). Interstitial Cajal cells (ICC) .According to Fulop et at.(2009),this hypothesis is supported by the fact that, according to the an immunhistochemical perspective, the GISTs and the ICC presents a common type of cell markers.Kindblom et al., (1998) pointed out that the interstitial Cajal cells (ICC) usually express CD117 -- c-kit. However, the marker having the highest level of specificity as well as sensitivity for the GISTs is represented by the same protein c-kit

CD117.The interstitial Cajal cells are usually localized in the digestive tract's muscular layer that includes places such as the sphincters, the areas around myenteric and submucosal nerve plexus and mostly at the distal part of the human stomach as well as the proximal small intestine. The cells have been noted to act as pacemakers for regulating the peristalsis mechanism as they lie between the smooth muscle cell and the autonomic nerve system.It is a n established fact that most of gastro intestinal stromal tumors ahave a strong association with the molecular anomalies that are evident in two genes (the c-kit which acts as a codifier of the kit protein) as well as the PDGFR (whose role is to encode PDGF receptor's A chain) (Pauls et al.,2005).The c-kit protein on the other hand is a transmembranary receptor that possesses tyrosine kinase action.The stem cells growth factor (SCF) acts as its special ligand. The interaction between this ligand and the c-kit protein is what determines the dimerisation of the protein. This then activates the phosphorilation as well as the activation of tyrosine kinase's the intracytoplasmic domain.

The activation of the above mentioned function then allows the kit protein to effectively phosphorilate the existing proteins within the cells in order to ensure that the transmission of the signals occurs. The main result of the activation of the c-kit protein is the induction of the cell proliferation process as well as the ceasing of the apoptosis. The genetic mutations that take place allow for the process of autophosphorilation occurring even when the ligand is absent. About 60 to 70% of most kit mutations that takes place in the GISTs entails the exon 11 (Fulop et at.,2009).This is regarded as a juxtamembrane domain having regulatory functions.The other forms of mutations that can be observed are exon 9 (thirteen percent),exon 13 (one percent) as well as exon 17 (one percent).Lasota et al., (2008) and Longley & Regueram., (2001) demonstrated that the mutations that take place in GISTs on the exon 11 form the most sensitive mutations to the imatinib treatment. Mutation of GISTs having mutations on both the exon 9 as well as 13 have a lower sensitivity.The GISTs mutations that represents the category of the tumors having a primary resistance to imatinib is the one on exon 17.

Mutations on the GISTs PDGFRA gene are highly localized at the levels of exons 12,14 and 18. Most of the GISTs that have mutations on this genes have been shown to have a gastric localization while possessing an epithelioid histological characteristic. Very few are however localized at the duodenum section. Close to 80% of the mutations involving PDGFRA are lo0calized at exon 18's level and they are a representation of GIST category that has primary resistance to the drug imatinib. Less frequent mutations (about 6%) are noted at the level of exon 14. This scenario is associated with prognosis which is less favorable. The rarest mutations occur at the level of exon12. They are however noted to be the most sensitive to the targeted and specific treatments.

The determination of the mutations in the day-to-day medical practice is never considered a necessary practice in order to establish a credible diagnosis. This is however not the case for GISTs with CD117 negative. The determination of the genetics has been shown to be useful in the establishment of the response of GISTs to treatment as well as the establishment of the evolution of the tumor as well as its prognosis.

The role played by cytogenetics in the progression of GISTs.

Liegl-Atzwanger, Fletcher and Fletcher (2010) explored the role that is played by cytogenetics in the progression of GIST.They pointed out that PDGFRA as well as KIT mutations are part of the early events in the development of GIST. The mutations are shown to occur irrespective of the signaling of the pathway by KIT within the tumor. Agaimy et al., (2008) as well as Kawanowa et al., (2006) have been observed in various rather microscopic and often "silent" incidental GIST that are detected in the gastrectomies that are carried out for other medical cases/reasons as well as in about 10 to 20% of the normal patient who are aged over 60 years. Findings like these indicates that mutations are involved in the proliferation as well as the encogenesis pf the GISTs. These processes however appear to bear limited importance in the malignant transformation of the GISTs (Corless et al.,2002). It is therefore appropriate to conclude that genetic hits / factors are integral in the progression of clinical tumors. About 2/3 of the PDGFRA and KIT mutant GISTs exhibit monosomy 14 or the partial loss of the 14q gene (Debiec-Rychter et al.,2001;Fukasawa et al.,2000;Isozaki, Hirota and Nakama,1995). Fukasawa et al.,(2000) pointed out that two regions of 14q, namely; 14q23 -- q24 and 14q11.2 -- q12 appears to hold or rather contain the genes that suppress the tumor that are indicated to be important in the early developmental stages of GISTs.

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.