Gastrointestinal stromal tumor - AbsoluteAstronomy.com

A gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal

Mesenchyme

Mesenchyme, or mesenchymal connective tissue, is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some are derived from other germ layers; e.g. some mesenchyme is derived from neural crest cells and thus originates from the ectoderm...

tumors of the gastrointestinal tract

Gastrointestinal tract

The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

(1-3% of all gastrointestinal malignancies). They are typically defined as tumors whose behavior is driven by mutations in the Kit

CD117

Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...

gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

or PDGFRA

PDGFRA

Alpha-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRA gene.-Interactions:PDGFRA has been shown to interact with PDGFRB, PLCG1, Sodium-hydrogen antiporter 3 regulator 1, Cbl gene, CRK, Caveolin 1 and PDGFC.-Further reading:...

gene, and may or may not stain positively for Kit.

Signs and symptoms

Patients present with trouble swallowing

Dysphagia

Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

, gastrointestinal hemorrhage or metastases

Metastasis

Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

(mainly in the liver). Intestinal obstruction is rare, due to the tumor's outward pattern of growth. Often, there is a history of vague abdominal pain

Abdominal pain

Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...

or discomfort, and the tumor has become rather large by time the diagnosis is made.

Generally, the definitive diagnosis is made with a biopsy

Biopsy

A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery.

Diagnosis

As part of the analysis, blood test

Blood test

A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....

s and CT scanning are often undertaken (see the radiology section).

A biopsy

Biopsy

sample will be investigated under the microscope. The histopathologist

Histopathology

Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...

identifies the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be found to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.

When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry

Immunohistochemistry

Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...

(specific antibodies

Antibody

An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

that stain the molecule CD117

CD117

Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...

(also known as c-kit) —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, vimentin and others). Other cells that show CD117 positivity are mast cell

Mast cell

A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s.

If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing

DNA sequencing

DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....

of Kit and PDGFRA can be used to prove the diagnosis.

Radiology

Barium fluoroscopic examinations (upper GI series

Upper GI series

Upper GI series, also upper gastrointestinal tract radiography, is a radiologic examination of the upper gastrointestinal tract. It consists of a series of X-ray images of the esophagus, stomach and duodenum...

and small bowel series) and CT

Computed tomography

X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...

are commonly used to evaluate the patient with upper abdominal pain

Abdominal pain

. Both are adequate to make the diagnosis of GIST, although small tumors may be missed, especially in cases of a suboptimal examination.

Small GISTs appear as intramural masses. When large (> 5 cm), they most commonly grow outward from the bowel. Internal calcification

Calcification

Calcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Causes:...

s may be present. As the tumor outstrips its blood supply, it can necrose

Necrosis

Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

internally, creating a central fluid-filled cavity that can eventually ulcerate

Peptic ulcer

A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

into the lumen of the bowel or stomach.

The tumor can directly invade adjacent structures in the abdomen. The most common site of spread is to the liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

. Spread to the peritoneum

Peritoneum

The peritoneum is the serous membrane that forms the lining of the abdominal cavity or the coelom — it covers most of the intra-abdominal organs — in amniotes and some invertebrates...

may be seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma

Lymphoma

Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

, malignant adenopathy (swollen lymph nodes) is uncommon (<10%).

Pathophysiology

GISTs are tumors of connective tissue

Connective tissue

"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

, i.e. sarcoma

Sarcoma

A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...

s; unlike most gastrointestinal tumors, they are nonepithelial

Epithelium

Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

. About 70% occur in the stomach

Stomach

The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

, 20% in the small intestine

Small intestine

The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

and less than 10% in the esophagus

Esophagus

The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...

. Small tumors are generally benign, especially when cell division

Mitosis

Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

rate is slow, but large tumors disseminate to the liver

Liver

, omentum

Omentum

Omentum may refer to:* greater omentum* lesser omentum...

and peritoneal cavity

Peritoneal cavity

The peritoneal cavity is a potential space between the parietal peritoneum and visceral peritoneum, that is, the two membranes that separate the organs in the abdominal cavity from the abdominal wall...

. They rarely occur in other abdominal organs.

Some tumors of the stomach and small bowel, referred to as leiomyosarcoma

Leiomyosarcoma

Leiomyosarcoma , aka LMS, is a malignant cancer of smooth muscle....

s (malignant tumor of smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

), would most likely be reclassified as GISTs today on the basis of immunohistochemical staining.

GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system

Autonomic nervous system

The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

of the intestine. They serve a pacemaker function in controlling motility

Motility

Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...

.

Most (50-80%) GISTs arise because of a mutation in a gene

Gene

called c-kit. This gene encodes a transmembrane receptor for a growth factor termed stem cell factor

Stem cell factor

Stem Cell Factor is a cytokine that binds to the c-Kit receptor . SCF can exist both as a transmembrane protein and a soluble protein...

(scf). The c-kit product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow

Bone marrow

Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

cells, mast cell

Mast cell

A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s, melanocyte

Melanocyte

-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...

s and several others. In the gut, however, a mass staining positive for CD117

CD117

Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...

is likely to be a GIST, arising from ICC cells.

The c-kit molecule

Molecule

A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

comprises a long extracellular domain

Membrane protein

A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...

, a transmembrane segment

Membrane protein

A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...

, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase

Tyrosine kinase

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

to activate other enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s. Mutations make c-kit function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process.

The tyrosine kinase

Tyrosine kinase

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

function of c-kit is vital in the therapy for GISTs, as described below.

Heritability

Although some families with hereditary

Genetic disorder

A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

GISTs have been described, most cases are sporadic.

In GIST cells, the c-kit gene is mutated approximately 85% to 90% of the time. 35% of the GIST cells with wildtype (i.e. not mutated) c-kit instead have a mutation in another gene, PDGFR-α (platelet derived growth factor receptor alpha

PDGFRA

), which is a related tyrosine kinase.

Mutations in the exon

Exon

An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...

s 11, 9 and rarely 13 and 17 of the c-kit gene are known to occur in GIST. D816V point mutation

Point mutation

A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

s in c-kit exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor. Mutations in c-kit and PDGFrA are mutually exclusive http://www.liferaftgroup.org/gist_genetics.html http://www.liferaftgroup.org/LondnPPT/Fletcher/Fletcher_files/frame.htm.

Therapy

Tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Nevertheless, all GIST tumors should be considered to have malignant potential and no GIST tumor can be correctly classified as "benign."
Surgery is the mainstay of therapy for nonmetastatic GISTs. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions.

Until recently, GISTs were notorious for being resistant to chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

, with a success rate of <5%. Recently, the c-kit tyrosine kinase

Tyrosine kinase

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

inhibitor imatinib

Imatinib

Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...

(Glivec/Gleevec), a drug initially marketed for chronic myelogenous leukemia

Chronic myelogenous leukemia

Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...

, was found to be useful in treating GISTs, leading to a 40-70% response rate in metastatic or inoperable cases.

The two year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.

Data presented at the 2007 ASCO meeting showed adjuvant treatment with imatinib following surgical resection of GIST tumors can significantly reduce the risk of disease recurrence (6% recurrence on imatinib vs. 17% without therapy at 12 months). The optimal duration of adjuvant therapy is currently unknown; trials are ongoing evaluating treatment durations of 1, 2, and 3 years.

Patients who develop resistance to imatinib may respond to the multiple tyrosine kinase inhibitor sunitinib

Sunitinib

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that was approved by the FDA for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor on January 26, 2006...

(marketed as Sutent).

The effectiveness of imatinib

Imatinib

and sunitinib

Sunitinib

depend on the genotype.

Epidemiology

GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. In all, there are approximately 3500-5000 cases of GIST per year in the United States. This makes GIST the most common form of sarcoma

Sarcoma

, which constitutes more than 70 types of cancer, but in all forms constitutes less than 1% of all cancer.

History

Until the 1990s, all nonepithelial

Epithelium

tumor

Tumor

A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s of the gastrointestinal tract

Gastrointestinal tract

The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

were called "gastrointestinal stromal tumors" from smooth muscle

Smooth muscle

origin. Histopathologists

Histopathology

Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...

generally did not distinguish between the types, as this did not affect either therapy or prognosis. Subsequently, CD34

Cluster of differentiation

The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...

, and later CD117 were identified as markers that could distinguish the various types.

External links

Prognosis in GIST ESUN (August 15, 2006)
GIST Support International
Life Raft Group International GIST Advocacy Organization
Project FLAG - GISTs that occur in families
American Cancer Society Patient Guide to GIST tumors.

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