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Soft tissue sarcomas arising from mesenchymal of the gastrointestinal tract.
The most common soft tissue sarcomas of the G.I. tract resulting primarily from KIT or PDGFRA activating mutations.
Incidence of at least 6000 new cases per year in the U.S.
The annual incidence is estimated to be between 0.68 and 0.78 per hundred thousand.
Fewer than 10 cases for 1 million person is diagnosed everywhere in the US.
Globally, 10-15 per million people who diagnosed each year with a GIST tumor, with the highest incidence in China, Taiwan, Korea, and Norway.
GIST has the highest incidence adults over 60, but certain familial mutations can predispose younger patients.
Men are affected one and a half times more than women.
Estimated 10-15 cases per million persons.
Overall incidence 6.8 cases per million.
In patients 40 years or less, the incidence is only 2.6 cases per million annually.
Accounts for 0.1-3% of all GI tumors.
Incidence between 6.8 and 20 per million population.
Gastric GIST represents about 60% of cases, small intestine 30%, duodenum 5%, rectum 4% esophagus, colon and appendix 1%.
It can rarely occur in extra intestinal sites.
Patients present with a variety of symptoms: satiety, abdominal discomfort due to pain or swelling, intraperitoneal hemorrhage, gastrointestinal, bleeding, fatigue related to anemia,annd uncommonly acute abdomen from tumor rupture, or G.I. obstruction.
Liver and/or the peritoneal surfaces of the most common sites of metastasis.
Lymph node metastasis are extremely rare.
Most patients present between 50 and 80 years of age.
Age-adjusted yearly incidence was 6.8 per million in SEER data from 1992-2000, with 54% men and 46% women (Tran T).
Most GISTs are local when detected and are treated with surgery.
Most important factors associated with prognosis are tumor mitotic rate and size, site of gastrointestinal tract involvement, and the presence of tumor rupture.
Median age at diagnosis ranges from 66-69 based on autopsy studies, and diagnosed about a decade later than in those with symptomatic disease.
The median age at diagnosis was 63 years in the study of 1765 patients with gastric GISTs (Miettinen M).
The mean age was 59 years in the study of 906 jejunal and ileal GISTs (Miettinen M).
Most common mesencyhmal tumors of the gastrointestinal tract.
Metastasis in the lungs, bone, another extra abdominal locations for observed only in advance cases.
The hallmark is that interstitial cells of Cajal acquire pathologic activating mutation in the c-KIT receptor tyrosine kinase, leading to activation of the pathway.
Occurs in all age groups, including newborns, but it is extremely rare in patients younger than 30 years of age.
Familial GIST syndrome is rare representing few within 5% of cases.
Familial GIST syndrome is an autosomal dominant disease caused by germ line mutations in KIT or PDGFRA.
Insertions, deletions, and missense mutations in the KIT, and PDGRFA occur in 85% of cases.
BRAF V600E missense mutations lead to approximately 1% of cases.
Most GISTs occurring in adults are driven by activating mutations in the KIT or PDGFRA genes, but 85% of GIST in children and 10-15% of GISTS in adults are KIT and PDGFRA mutation negative, referred to as wild type GIST.
One in 5.8 patients develop additional malignancies before and after the diagnosis (Sickick JK).
Patients with GIST have a 44% increase prevalence of cancers occurring before diagnosis and 66% higher incidence of developing cancers after diagnosis.
Patients with GIST tumors smaller than 10 cm have a higher probability of a second cancer than patients with larger tumors.
Increased occurrence with diagnosis of GIST are sarcomas, neuroendocrine tumors, colorectal cancers, non-Hodgkin’s lymphoma, esophageal adenocarcinoma, melanoma, prostate cancer, small bowel cancer, thyroid cancer, gastric cancer, renal cancer, hepatobiliary cancer pancreatic cancer non-small cell lung cancer and transitional cell carcinoma of the bladder.
Other inherited forms of GIST include deficiencies in the succinate dehydrogenase complex, Carney-Stratakis syndrome, and type I neurofibromatosis
Probably arise from the interstitial cells of Cajal, the pacemaker cells of the autonomous movement of the gastrointestinal tract.
Primary lesion can rise anywhere in the G.I. tract, but most commonly in the stomach (50-70%), or small bowel (25%-30%).
The malignant potential of GIST varies from minimal in micro GIST to aggressive cancer.
Other sites of lesions include the colon, rectum, mesentery, omentum, retro peritoneum, pelvis and esophagus.
GIST are friable tumors with a propensity to rupture.
Rectal primary lesions are uncommon, as are lesions of the colon.
3-5% of patients have PDGF receptor alpha.
Up to 50% relapse with surgery alone within 5 years and eventually die of the disease (Ng H, DeMatteo RP).
Most frequent sites of initial recurrence are the peritoneal surface and the liver.
Less than 1% of cases originating in the esophagus or appendix.
Extra gastrointestinal stromal tumors have an aggressive course similar to small intestinal lesions.
Interstitial cells of Cajal are KIT positive and GIST may be a neoplasm from these cells.
Blockade of KIT signaling with tyrosine kinase inhibitors lead to clinical responses in the nearly 80%of patients.
50% of patients with advanced disease acquire resistance to imatinib within 2 years.
Some studies suggest this tumor may arise from interstitial mesenchymal precursor stem cells.
Driven mainly by activating mutations that involve c-kit and platelet derived growth factor receptor-alpha, two type III receptor tyrosine kinases located on chromosome 4.
Tumor probably arises from mutations in precursor cells that normally give rise to the interstitial cells of Cajal.
c-kit and platelet derived growth factor receptor activating mutations occur early and are mutually exclusive events.
c-kit mutations correlate with high-risk tumors suggesting that molecular changes contribute to progression of disease.
Most lesions express the protein product of the KIT proto-oncogene.
Immunohistochemical staining of the 145-kDa transmembrane glycoprotein, KIT (CD117) confirms the diagnosis.
KIT(CD117) is expressed in more than 95% of GIST‘s, 80% of these patients have an activated mutation in the gene encoding for the KIT receptive tyrosine kinase, in 5 to 10% the mutation is in the gene in coding for PDGFR Alpha receptive tyrosine kinase.
10-15% of ‘s are KIT and PDGFRalpha are wild tape, and in 10-15% of these tumors BRAF mutations can occur.
Small GISTs of only a few millimeters in diameter are common in the general population, and autopsy studies in Germany found such lesions in 22.5% of individuals older than 50 years (Agaimy A).
Small GISTs referred to as mini-GISTs are immunopositive for KIT, and frequently contain an oncogenic mutation in the KIT or the PDGFRA gene (Agaimy A).
The above findings suggest that most small GISTs do not progress into large macroscopic tumors.
A subset of tumors are malignant with 40% thought to be metastatic.
Approximately 85-90% of lesions associated with gain of function KIT gene mutations that lead to activation of KIT kinase activity.
Approximately 5% of lesions associated with analogous gain of function mutations in PDGFRA, the gene encoding platelet derived growth factor receptor α.
Less than 10% of lesions have no identifiable receptor tyrosine kinase mutations.
Activating mutations of KIT and PDGFRA the driving forces in the development and progression of the malignant phenotype of most tumors.
Failure of the most tyrosine kinase inhibitors in the GIST cells acquire a secondary mutation that allow them to circumvent the blockade in KIT signaling, often utilizing other cellular pathways.
Express CD34 (a transmembrane glycoprotein and a hematopoietic progenitor cell antigen found in mesenchymal cells) in 60-70% of cases.
Make up about 5% of soft tissue sarcomas and 0.1-3% of gastrointestinal malignancies.
Accounts for 2% of gastric tumors, 14% of small intestinal tumors and 0.1% of colon tumors.
Appear most commonly during the sixth and seventh decades of life, but can occur in the pediatric population.
Uncommon in patients younger than 40 years and rare in children.
Rare sites of gastrointestinal origin include gall bladder, appendix, and omentum can occur.
1-3% of gastrointestinal tumors.
10-30% of patients are diagnosed incidentally and may be asymptomatic.
Difficult to classify patients, wide variability in clinical behavior and variability in the management contribute to the wide 5-year survival rate range from 19% to 56% overall and from 32% to 63% following resection.
Multiple imaging modalities can identify GIST; endoscopic, ultrasound with fine needle aspiration biopsy is the preferred diagnostic test.
Metastatic lesions are typically found in the liver or peritoneum.
Complete surgical resection is presently the only means of cure.
Complete resection of all tumor is possible in 48-89% of cases.
After complete resection, 3 and 5-year survival rates are 54% and 42%, respectively, as compared with 13% and 9% after incomplete resection.
Tumors with more than 1 mitosis and size larger than 5 cm have a poor prognosis, with decreased survival, and increased local and/or distant recurrence.
Tumors with the mitotic rate of five or fewer mitoses per 50 HPF and a size of less than 5 cm or less in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate greater than five mitoses per 50 HPF and a size greater than 10 cm, and larger tumors have a recurrence rate of up to 86%.
Between 10 and 30% are highly malignant.
Recurrence rate of about 40%.
Most frequent symptoms are pain, discomfort, a palpable mass, and bleeding.
Patients with bleeding are most likely to undergo complete resection of the tumor.
Bleeding is the most common symptom occurring in approximately 50% of patients.
Obstruction of the gastrointestinal tract present in 10-30% of patients
About 20% of patients are asymptomatic.
Almost half of patients have metastases at presentation.
Liver most common site of metastases with a reported incidence of 55-72% in patients with recurrent disease.
Liver metastases is a major determinant of survival and resection of such metastases is beneficial.
1 and 3 year survival rates for patients with liver metastases that underwent complete resection of all visible disease was 90% and 58%, respectively in one series.
With long-term follow-up a high incidence of recurrences and death can be anticipated emphasizing follow-up should be extended well beyond the typical 5-year endpoint.
All lesions even those less than 2 cm and with low mitotic rates have potential to metastasize.
C-kit positive tumor.
About 80% of GISTs have mutations in the KIT gene, causing activation of the kinase and stimulates signaling through downstream pathways that support tumor growth.
Mutations in a KIT homologue, platelet-derived growth factor receptor alpha (PDGFRA) accounts for 10% of GISTs.
Approximately 10% of GIST tumors are wild-type, a heterogeneous group with mutations and other genes with the MAP kinase pathway or have defects in succinate dehydrogenase activity related to mutations of chains encoding this complex.
The principal goal of surgery is to remove the tumor completely with clear margins and an intact pseudocapsule.
For microscopically positive margins, re-resection is not required.
Most KIT mutations are deletion mutations in Econ 11, and these deletions frequently span the critical codons 557 and/or 558.
KIT exon 11 mutations that involve codons 557 and/or 558 are associated with poor prognosis in patients treated with surgery.
Some other KIT mutations, such as exon 11 insertion and duplication mutations and PDGFRA mutations, are generally associated with a favorable survival.
Wild-type GIST tumors are less sensitive to imatinib and other TKIs.
The response rate of imatinib to GIST-KIT exon mutations vary, but the KITS exon 11 mutation reduces the risk of death by greater than 95%.
GIST with KIT exon 9 mutation have a lowered response and strongest adverse prognostic factor for progression and death.
Resistant to chemotherapy and radiation therapy.
GIST does not generally respond to standard chemotherapy or radiation.
RECIST criteria are insensitive in evaluating these lesions since treatment takes several months to decrease tumor size and fails to shrink the tumor 50% of the time.
Immunohistochemical marker KIT (CD117) overexpression drives the neoplastic growth in GISTs.
Immunohistological staining for CD34 and CD117 are needed for positive identification and diagnosis.
Grossly tumors are spherical and well demarcated and appear to arise from the muscularis propria layer of the gastrointestinal wall projecting exophytically or intraluminally.
Patients with advanced GIST usually respond to imatinib and other agents that inhibit KIT and PDGFRA, but most patients will develop progressive disease.
Receptor tyrosine kinase inhibitor imatinib mesylate first effective therapy for recurrent or metastatic GISTs.
Up to 90% of patients with metastatic disease respond or achieve durable stable disease with imatinib.
About half of GIST patients who initially respond to imatinib develop resistance to the drug in the first two years.
Complete remissions with imatinib are rare, and up to 50% of patients develop resistance during the course of the first 2 years of systemic therapy (Heinrich MC et al).
The length of time to recurrence is the main predictor of survival after resection of a GIST recurrence, with disease-free interval of greater than 2 years associated with an improved overall survival.
Patients with metastatic disease treated with imatinib are expected to live a median of 5 years compared to only 1 year in the pre imatinib era.
Most patients treated with imatinib eventually relapse with one mechanism being acquired resistance via KIT gene mutation that prevents imatinib binding to the kinase.
Achieving stable disease with imatinib is as good as achieving an actual response in terms of how long a patient lives.
Complete response with imatinib is rare and approximately half of patients with initial response develop progression within 2 years.
With imatinib most patients respond fairly quickly, but a number of patients do not achieve maximum response until 6 months.
Other tyrosine kinase inhibitors then imatinib like sunitinib, regoreafenib and ripretinib others have demonstrated benefits in imatinib setting, but most patients eventually become resistant.
Response causes changes in tumor density, tumor nodules and tumor vessels.Choi criteria for responses include; complete remission-disappearance of al lesion and no new lesions, partial response-requires a 10% or more decrease in tumor size and a 15% or more decrease in tumor density on a CT scan, stable disease-does not meet criteria for complete or partial response or progressive disease-progressive disease-an increase in size of lesions of 10% or more, does not meet criteria of partial response, new lesions, and new intraluminal nodules or increases in size of existing intraluminal tumor nodules.
CT scans allow for assessment of tumor for change in size and density.
PET scan should be performed when CT findings are inconclusive for inconsistent.
A decrease in PET scan uptake is a sensitive early indicator of response that predicts long-term clinical benefit of treatment with the use of imatinib.
Up-regulation of insulin-like growth factor binding protein 3 (IGFBP3) occurs in imatinib sensitive GIST cells.
IGFBP3 is a major protein involved in the sequestration of insulin like growth factor (IGF) to the IGF receptor (IGFR)
IGFBP3 is induced by tumor suppressor gene p53 and localizes to the nucleus of the tumor cell and exerts an inhibition of cell proliferation and induction of apoptosis.
In a phase III double blind, randomized trial compared 1 year of adjuvant therapy with imatinib versus placebo in patients resected with localized primary KIT+ GIST: at a median follow-up of 19.7 months 8% of imatinib group recurred, and 20% of the placebo recurred or died (DeMatteo RP).
In the above study during the year of drug study only 1 recurrence occurred compared to 41 in the placebo group: 6 months after discontinuing therapy the recurrence rate increased in the imatinib group suggesting prolonging adjuvant therapy will be beneficial.
A phase III trial of adjuvant imatinib in high risk patients at 3 years of treatment showed significant improvement overall recurrence free survival compared to one year of treatment, suggesting 3 years of treatment will become the new standard of care for high risk patients.
In a randomized study of 3 years of adjuvant imatiniib improved relapse free survival of GIST patients with a high estimated risk of recurrence after surgery compared with one year of the agent, with 65.6% and 47.5% of the patients, respectively, being alive without recurrence 5 years after study entry (Joensuu H et al).
In study of 400 patients with GIST at high-risk for recurrence randomly assigned to one or 3 years of imatinib 400 mg/d after surgery: After a median followup of 54 months, 5 year recurrence free survival higher at 3 year group at 66%, compared to the group treated for one year at 48%, and five-year overall survival was 92% at 82%, respectively (Joensuu H et al).
In disease refractory to imatinib, sunitinib and sorafenib are effective agents.
Regorafenib improves progression free survival.
In a phase 3 GRID trial Regorafenib reduced the risk of disease progression by 73% in patients with GIST tumor’s that exhausted all other treatment options(Demetrius GD et al).
90% of patients with GIST tumors treaty with Imatinib or sunitinib become refractory, but Regorafenib allows the drug to inhibit the KIT and PDGFR-alpha mutations that drive the tumor.
Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs.
Treatment is not recommended in an imatinib-insensitive PDGFRA D842V-mutated GIST.
Median progression free survival of Imatinib treated patients with the PDGFRA D842V-mutated GIST is only 2.8 months compared to 28,5 months with other PDGRA associated lesions (Cassier PA et al).
During adjuvant treatment, patients should be be clinically reassessed at 1- to 3-month intervals.
Computerized tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation.
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, with an incidence of ~10 cases per million per year.
The development of GISTs is largely driven by mutations in the KIT gene and, to a lesser extent, the PDGFRA gene.
Thirty to fifty percent of patients with surgically resected primary GISTs relapse within 5 years, and high-risk patients tend to recur even earlier.
Imatinib is the mainstay of therapy in metastatic GISTs.
1st It is a potent inhibitor of the KIT and PDGFR receptors, which are the main molecular drivers of GIST.
Survival outcomes in patients with metastatic GIST have increased ~3-fold since the introduction of tyrosine kinase inhibitors and the median survival in advanced disease has extended to 57 months.
The ACOSOG Z9001 a large randomised, placebo-controlled trial demonstrated a relapse-free survival benefit of adjuvant imatinib 400 mg/day for 1-year duration: after a median follow-up of 19.7 months, the estimated 1-year RFS was 98% in the imatinib arm compared with 83% in the placebo arm.
Subanalyses of the Z9001 trial by mutation subtype showed a statistically significant difference in 2-year RFS favouring the treatment arm for patients with KIT exon 11 and PDGFRA mutations, but not for wild-type and KIT exon 9-mutated GISTs.
The Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology [Arbeitsgemeinschaft Internistische Onkologie (AIO)] reported results of a large randomised, controlled trial comparing adjuvant imatinib for 3 years with adjuvant imatinib for 1 year in patients with: tumor diameter >10 cm or mitosis count >10/50 HPF, or size >5 cm and mitosis count >5/50 HPFs or tumor rupture spontaneously or at surgery: At 5 years with a median follow-up of 54 months, 42% of patients in the 1-year treatment group experienced GIST recurrence, compared with 25% of patients in the 3-year treatment group.
The relapse free survival of patients receiving 3 years of imatinib therapy versus 1 year was 87% versus 60% at 3 years of follow-up, and 66% versus 48% at 5 years of follow-up, and that in both arms, there is a marked increase in GIST recurrences following imatinib discontinuation, introducing the possibility that even longer duration of adjuvant therapy may yield additional clinical benefit.
The overall survival of patients with 3 years of imatinib therapy versus 1 year was 96% versus 94% at 3 years of follow-up and 92% versus 82% at 5 years of follow-up, representing a >50% reduction in the number of patients dying in the 3-year adjuvant therapy arm when compared with the 1-year treatment group.
Compared with 1 year, 3 years adjuvant imatinib improves RFS and OS in this population of high risk GIST tumors.
Adjuvant imatinib therapy should be considered a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs.
Mitosis rate, tumor size and small bowel location are independently associated with poor relapse free survival.
The goal of surgery in primary GISTs is complete removal of the primary tumour (R0 resection), with lower recurrence rates than with R1resections.
Tumors where only R1 section is possible are likely high-risk.
Tumor rupture at the time of surgery may have risk of progression as metastatic disease, and such patients should be considered for lifelong tyrosine kinase inhibitor therapy.
Patients with tumor rupture have 80% to 100% risk of recurrence.
The approved imatinib dose for adjuvant therapy is 400 mg/day.
In the metastatic setting, evidence supports the dose of 800 mg/day of imatinib in the treatment of patients with KIT exon 9-mutated GIST.
Mutational status provides prognostic information, and adjuvant therapy is not recommended in imatinib-insensitive D842V-mutated GIST, regardless of risk.
Adjuvant imatinib treatment is considered in wild-type GISTs, lacking a detectable KIT or PDGFRA mutation, which may be less sensitive to imatinib than most GISTs with a mutation.
Cases of neurofibromatosis type 1-associated GIST strongly express KIT, and are usually indolent in nature.
The optimal duration of adjuvant imatinib therapy is still not known, but treatment for 3 years of duration as a standard of care in high-risk operable GISTs is recommended.
Patients who discontinue treatment in the metastatic setting and progress can achieve response upon retreating with imatinib.
CT or magnetic resonance imaging (MRI) of the pelvis or abdomen to detect recurrence is recommended every 6 months during adjuvant therapy.
The high risk of recurrence following discontinuation of adjuvant imatinib is 2-years.
Recurrence is rare after the 10th year of follow-up.
Long-term survival of patients with metastatic GIST is associated with low tumor burden, making early detection of GIST recurrence important.
Patients with plasma imatinib levels <1100 ng/mL have a lower response rates and a shorter time to disease progression compared to patients with plasma levels >1100 ng/ml, and there is a wide interpatient variability in plasma levels.
Severe side-effects, grade 3–4, occurred in one-third of patients treated with adjuvant imatinib therapy for 3 years, compared with 20% of patients treated for 1 year.
Over 3 years, the most frequently occurring adverse events were: anemia (80%) and periorbital edema (74%), elevated lactate dehydrogenase (60%), diarrhea (54%), nausea (51%), muscle cramps (49%), fatigue (48%) and leukopenia (47%).
In the SSGXVIII/AIO trial, 25.8% and 12.6% of the patients assigned to the 36-month and 12-month arms, respectively, discontinued imatinib for another reason than GIST recurrence.
The optimal duration of adjuvant therapy in GISTs is not known, and speculation is that some patients may benefit from lifelong therapy.
Pazopanib hows significant activity in GIST in patients resistant to imatinib and sunitinib (PAZOGIST Study).
Avapritinib is a kinase inhibitor that is approved for the treatment of unresectable or metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations.
Sunitinib and Stivarga are additional effctive agents.
TKI resistance develops through the emergence of secondary resistance, mutations in KIT.
TKI response varies with different molecular manifestations of KIT and PDGFRA.
Wild type GIST is generally unresponsive to kinase inhibitor therapy.
WT GIST primarily affects young females, and is multifocal, but is indolent.
WT GIST primary tumor is generally gastric in location.
WT GIST along with paraganglioma is a component of the Carney-Stratakis syndrome, an inherited predisposition syndrome caused by germline mutations in this succinyl dehydrogenase subunit B,C or D.