Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Computed tomography radiogenomics:A potential tool for prediction of molecular subtypes in gastric stromal tumor

BACKGROUND Preoperative knowledge of mutational status of gastrointestinal stromal tumors(GISTs)is essential to guide the individualized precision therapy.AIM To develop a combined model that integrates clinical and contrast-enhanced computed tomography(CE-CT)features to predict gastric GISTs with specific genetic mutations,namely KIT exon 11 mutations or KIT exon 11 codons 557-558 deletions.METHODS A total of 231 GIST patients with definitive genetic phenotypes were divided into a training dataset and a validation dataset in a 7:3 ratio.The models were constructed using selected clinical features,conventional CT features,and radiomics features extracted from abdominal CE-CT images.Three models were developed:ModelCT sign,modelCT sign+rad,and model CTsign+rad+clinic.The diagnostic performance of these models was evaluated using receiver operating characteristic(ROC)curve analysis and the Delong test.RESULTS The ROC analyses revealed that in the training cohort,the area under the curve(AUC)values for model_(CT sign),model_(CT sign+rad),and modelCT_(sign+rad+clinic)for predicting KIT exon 11 mutation were 0.743,0.818,and 0.915,respectively.In the validation cohort,the AUC values for the same models were 0.670,0.781,and 0.811,respectively.For predicting KIT exon 11 codons 557-558 deletions,the AUC values in the training cohort were 0.667,0.842,and 0.720 for model_(CT sign),model_(CT sign+rad),and modelCT_(sign+rad+clinic),respectively.In the validation cohort,the AUC values for the same models were 0.610,0.782,and 0.795,respectively.Based on the decision curve analysis,it was determined that the model_(CT sign+rad+clinic)had clinical significance and utility.CONCLUSION Our findings demonstrate that the combined modelCT_(sign+rad+clinic)effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions.This combined model has the potential to be valuable in assessing the genotype of GISTs.

Gastric IgG4-related disease mimicking a gastrointestinal stromal tumor in a child: A case report

BACKGROUND Gastric IgG4-related disease(IgG4-RD)is rarely encountered in clinical practice,and especially more so among pediatric patients.To our knowledge,this is the first report of IgG4-RD presenting as a calcifying gastric mass in a child.We describe how this entity was difficult to differentiate from a gastrointestinal stromal tumor(GIST)imaging-based approaches.Therefore,this case highlights the importance of considering IgG4-RD in the differential diagnosis of gastric tumor before performing surgical resection,especially to distinguish it from malignancy to avoid unnecessary surgery.CASE SUMMARY The patient suffered from epigastric pain for several days.Panendoscopy and computed tomography scan revealed a submucosal tumor.Differential diagnoses included GIST,leiomyoma,teratoma,and mucinous adenocarcinoma.However,laparoscopic proximal gastrectomy allowed for the definitive diagnosis of IgG4-related stomach disease.CONCLUSION We emphasize the importance of considering IgG4-RD in the differential diagnosis of gastric submucosal tumors before performing surgical resection.

Postoperative encapsulated hemoperitoneum in a patient with gastric stromal tumor treated by exposed endoscopic full-thickness resection: A case report

BACKGROUND Gastric stromal tumors,originating from mesenchymal tissues,are one of the most common tumors of the digestive tract.For stromal tumors originating from the muscularis propria,compared with conventional endoscopic submucosal dissection(ESD),endoscopic full-thickness resection(EFTR)can remove deep lesions and digestive tract wall tumors completely.However,this technique has major limitations such as perforation,postoperative bleeding,and post-polypectomy syndrome.Herein,we report a case of postoperative serous surface bleeding which formed an encapsulated hemoperitoneum in a patient with gastric stromal tumor that was treated with exposed EFTR.Feasible treatment options to address this complication are described.CASE SUMMARY A 47-year-old male patient had a hemispherical protrusion found during gastric endoscopic ultrasonography,located at the upper gastric curvature adjacent to the stomach fundus,with a smooth surface mucosa and poor mobility.The lesion was 19.3 mm×16.1 mm in size and originated from the fourth ultrasound layer.Computed tomography(CT)revealed no significant evidence of lymph node enlargement or distant metastasis.Using conventional ESD technology for mucosal pre-resection,exposed EFTR was performed to resect the intact tumor in order to achieve a definitive histopathological diagnosis.Based on its morphology and immunohistochemical expression of CD117 and DOG-1,the lesion was proven to be consistent with a gastric stromal tumor.Six days after exposed EFTR,CT showed a large amount of encapsulated fluid and gas accumulation around the stomach.In addition,gastroscopy suggested intracavitary bleeding and abdominal puncture drainage indicated serosal bleeding.Based on these findings,the patient was diagnosed with serosal bleeding resulting in encapsulated abdominal hemorrhage after exposed EFTR for a gastric stromal tumor.The patient received combined treatments,such as hemostasis under gastroscopy,gastrointestinal decompression,and abdominal drainage.All examinations were normal within six months of follow-up.CONCLUSION This patient developed serous surface bleeding in the gastric cavity following exposed EFTR.Serosal bleeding resulting in an encapsulated hemoperitoneum is rare in clinical practice.The combined treatment may replace certain surgical techniques.

Relationship between multi-slice computed tomography features and pathological risk stratification assessment in gastric gastrointestinal stromal tumors

BACKGROUND Computed tomography(CT)imaging features are associated with risk stratification of gastric gastrointestinal stromal tumors(GISTs).AIM To determine the multi-slice CT imaging features for predicting risk stratification in patients with primary gastric GISTs.METHODS The clinicopathological and CT imaging data for 147 patients with histologically confirmed primary gastric GISTs were retrospectively analyzed.All patients had received dynamic contrast-enhanced CT(CECT)followed by surgical resection.According to the modified National Institutes of Health criteria,147 lesions were classified into the low malignant potential group(very low and low risk;101 lesions)and high malignant potential group(medium and high-risk;46 lesions).The association between malignant potential and CT characteristic features(including tumor location,size,growth pattern,contour,ulceration,cystic degeneration or necrosis,calcification within the tumor,lymphadenopathy,enhancement patterns,unenhanced CT and CECT attenuation value,and enhancement degree)was analyzed using univariate analysis.Multivariate logistic regression analysis was performed to identify significant predictors of high malignant potential.The receiver operating curve(ROC)was used to evaluate the predictive value of tumor size and the multinomial logistic regression model for risk classification.RESULTS There were 46 patients with high malignant potential and 101 with low-malignant potential gastric GISTs.Univariate analysis showed no significant differences in age,gender,tumor location,calcification,unenhanced CT and CECT attenuation values,and enhancement degree between the two groups(P>0.05).However,a significant difference was observed in tumor size(3.14±0.94 vs 6.63±3.26 cm,P<0.001)between the low-grade and high-grade groups.The univariate analysis further revealed that CT imaging features,including tumor contours,lesion growth patterns,ulceration,cystic degeneration or necrosis,lymphadenopathy,and contrast enhancement patterns,were associated with risk stratification(P<0.05).According to binary logistic regression analysis,tumor size[P<0.001;odds ratio(OR)=26.448;95%confidence interval(CI):4.854-144.099)],contours(P=0.028;OR=7.750;95%CI:1.253-47.955),and mixed growth pattern(P=0.046;OR=4.740;95%CI:1.029-21.828)were independent predictors for risk stratification of gastric GISTs.ROC curve analysis for the multinomial logistic regression model and tumor size to differentiate high-malignant potential from low-malignant potential GISTs achieved a maximum area under the curve of 0.919(95%CI:0.863-0.975)and 0.940(95%CI:0.893-0.986),respectively.The tumor size cutoff value between the low and high malignant potential groups was 4.05 cm,and the sensitivity and specificity were 93.5%and 84.2%,respectively.CONCLUSION CT features,including tumor size,growth patterns,and lesion contours,were predictors of malignant potential for primary gastric GISTs.

Optical second-harmonic generation imaging for identifying gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors arising in the digest tract.It brings a challenge to diagnosis because it is asymptomatic clinically.It is well known that tumor development is often accompanied by the changes in the morphology of collagen fibers.Nowadays,an emerging optical imaging technique,second-harmonic generation(SHG),can directly identify collagen fibers without staining due to its noncentrosymmetric properties.Therefore,in this study,we attempt to assess the feasibility of SHG imaging for detecting GISTs by monitoring the morphological changes of collagen fibers in tumor microenvironment.We found that collagen alterations occurred obviously in the GISTs by comparing with normal tissues,and furthermore,two morphological features from SHG images were extracted to quantitatively assess the morphological difference of collagen fibers between normal muscular layer and GISTs by means of automated image analysis.Quantitative analyses show a significant difference in the two collagen features.This study demonstrates the potential of SHG imaging as an adjunctive diagnostic tool for label-free identification of GISTs.

Neurofibromatosis type 1 with multiple gastrointestinal stromal tumors:A case report

BACKGROUND Neurofibromatosis type 1(NF1)is characterized by café-au-lait patches on the skin and the presence of neurofibromas.Gastrointestinal stromal tumor(GIST)is the most common non-neurological tumor in NF1 patients.In NF1-associated GIST,KIT and PDGFRA mutations are frequently absent and imatinib is ineffective.Surgical resection is first-line treatment.CASE SUMMARY A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass.Physical examination was notable for multiple café-au-lait patches and numerous subcutaneous soft nodular masses of the skin of the head,face,trunk,and limbs.Her abdomen was soft and nontender.No masses were palpated.Digital rectal examination was unremarkable.Abdominal computed tomography was suspicious for GIST or solitary fibrous tumor.Laparoscopy was performed,which identified eight well-demarcated masses in the jejunum.All were resected and pathologically diagnosed as GISTs.The patient was discharged on day 7 after surgery without complications.No tumor recurrence was evident at the 6-mo follow-up.CONCLUSION Laparoscopy is effective for both diagnosis and treatment of NF1-associated GIST.

Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors:A case report

BACKGROUND Sunitinib,a multi-targeted tyrosine kinase inhibitor(TKI),has been approved for the salvage treatment of gastrointestinal stromal tumors(GIST).Hyperammonemic encephalopathy is a rare but severe complication of sunitinib use.Here,we present the case of a 66-year-old male with metastatic GIST without underlying liver cirrhosis who developed sunitinib-induced hyperammonemic encephalopathy.CASE SUMMARY A 66-year-old male with metastatic GIST was admitted because of reduced consciousness.Imatinib was administered as the first-line systemic therapy.He experienced repeated episodes of peritonitis due to tumor perforation,and surgery was performed.Progressive disease was confirmed based on increased liver metastasis,and sunitinib was initiated as a salvage treatment.However,23 d after the third course of sunitinib,he presented to the emergency room with an episode of altered consciousness and behavioral changes.Based on the patient clinical history and examination findings,sunitinib-induced encephalopathy was suspected.Sunitinib was discontinued,and the patient was treated for hyperammonemia.The patient had a normal level of consciousness four days later,and the serum ammonia level gradually decreased.No further neurological symptoms were reported in subsequent follow-ups.CONCLUSION TKI-induced hyperammonemic encephalopathy is potentially life-threatening.Patients receiving TKIs experiencing adverse reactions should undergo systemic evaluation and prompt treatment.

TATA-box-binding protein-associated factor 15 is a novel biomarker that promotes cell proliferation and migration in gastrointestinal stromal tumor

BACKGROUND Gastrointestinal stromal tumor(GIST)is a common neoplasm with high rates of recurrence and metastasis,and its therapeutic efficacy is still not ideal.There is an unmet need to find new molecular therapeutic targets for GIST.TATA-boxbinding protein-associated factor 15(TAF15)contributes to the progress of various tumors,while the role and molecular mechanism of TAF15 in GIST progression are still unknown.AIM To explore new molecular therapeutic targets for GIST and understand the biological role and underlying mechanisms of TAF15 in GIST progression.METHODS Proteomic analysis was performed to explore the differentially expressed proteins in GIST.Western blotting and immunohistochemical analysis were used to verify the expression level of TAF15 in GIST tissues and cell lines.Cell counting kit-8,colony formation,wound-healing and transwell assay were executed to detect the ability of TAF15 on cell proliferation,migration and invasion.A xenograft mouse model was applied to explore the role of TAF15 in the progression of GIST.Western blotting was used to detect the phosphorylation level and total level of RAF1,MEK and ERK1/2.RESULTS A total of 1669 proteins were identified as differentially expressed proteins with 762 upregulated and 907 downregulated in GIST.TAF15 was selected for the further study because of its important role in cell proliferation and migration.TAF15 was significantly over expressed in GIST tissues and cell lines.Overexpression of TAF15 was associated with larger tumor size and higher risk stage of GIST.TAF15 knockdown significantly inhibited the cell proliferation and migration of GIST in vitro and suppressed tumor growth in vivo.Moreover,the inhibition of TAF15 expression significantly decreased the phosphorylation level of RAF1,MEK and ERK1/2 in GIST cells and xenograft tissues,while the total RAF1,MEK and ERK1/2 had no significant change.CONCLUSION TAF15 is over expressed in GIST tissues and cell lines.Overexpression of TAF15 was associated with a poor prognosis of GIST patients.TAF15 promotes cell proliferation and migration in GIST via the activation of the RAF1/MEK/ERK signaling pathway.Thus,TAF15 is expected to be a novel latent molecular biomarker or therapeutic target of GIST.

Rectal gastrointestinal stromal tumors:Imaging features with clinical and pathological correlation

AIM:To investigate computed tomography(CT) and magnetic resonance imaging(MRI) manifestations of rectal gastrointestinal stromal tumors(GISTs) in order to enhance the recognition of these rare tumors.METHODS:Fourteen patients with pathologically proven rectal GISTs were retrospectively reviewed.Patient histories were retrospectively reviewed for patient age,gender,presenting symptoms,endoscopic investigations,operation notes and pathologic slides.All tumors were evaluated for CD117,CD34 expression,and the tumors were stratified according to current criteria of the National Institutes of Health(NIH).In all cases the first pre-operation imaging findings(CT and MRI,n = 3;MRI only,n = 8;CT only,n = 3) were analyzed by two experienced radiologists by consensus,which include:tumor size,shape,CT density(hypodense,isodense and hyperdense),MRI signal intensity(hypointense,isointense and hyperintense),epicenter(intraluminal or extraluminal),margin(well-defined or ill-defined),internal component(presence of calcifications,necrosis,hemorrhage or ulceration),pattern and degree of enhancement,invasion into adjacent structures.After review of the radiologic studies,clinical and pathological findings were correlated with radiological findings.RESULTS:The patients,13 men and 1 woman,were aged 31-62 years(mean = 51.5 ± 10.7 years).The most common initial presentation was hematochezia(n = 6).The mean tumor diameter was 5.68 ± 2.64 cm(range 1.5-11.2 cm).Eight lesions were round or oval,and 6 lesions were irregular.Eleven lesions were welldefined and 3 had ill-defined margins.Ten tumors were extraluminal and 4 were intraluminal.The density and MR signal intensity of the solid component of the lesions were similar to that of muscle on unenhanced CT(n = 6) and T1-weighted images(n = 11),and hyperintense on T2-weighted MR images.Calcification was detected in 2 tumors.Following intravenous injection of contrast media,3 lesions had mild enhancement and 11 lesions had moderate enhancement.Enhancement was homogenous in 3 lesions and heterogeneous in 11.In 1 of 11 patients who underwent both CT and MRI,the tumor was homogenous on CT scan and heterogeneous on MRI.Eight patients were classified as high risk according to the modified recurrent risk classification system of NIH.CONCLUSION:Rectal GISTs usually manifest as large,well-circumscribed,exophytic masses with moderate and heterogeneous enhancement on CT and MRI.The invasion of adjacent organs,bowel obstruction and local adenopathy are uncommon.

A gist of gastrointestinal stromal tumors: A review

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mes-enchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularlytargeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors.

Molecular basis and management of gastrointestinal stromal tumors

Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for firstand secondline treatment of metastatic and unresectable GISTs. In this article, we will review the molecular pathogenesis of GISTs followed by a discussion of imatinib and sunitinib’s role in the treatment of GISTs. Finally, we will introduce novel therapeutic options for imatiniband sunitinib-resistant GISTs.

New-style laparoscopic and endoscopic cooperative surgery for gastric stromal tumors

AIM: To evaluate the feasibility and safety of a new style of laparoscopic and endoscopic cooperative surgery (LECS), an improved method of laparoscopic intragastric surgery (LIGS) for the treatment of gastric stromal tumors (GSTs). METHODS: Six patients were treated with the newstyle LECS. Surgery was performed according to the following procedures: (1) Exposing and confirming the location of the tumor with gastroscopy; (2) A laparoscopy light was placed in the cavity using the trocar at the navel, and the other two trocars penetrated both the abdominal and stomach walls; (3) With gastroscopy monitoring, the operation was carried out in the gastric lumen using laparoscopic instruments and the tumor was resected; and (4) The tumor tissue was removed orally using a gastroscopy basket, and puncture holes and perforations were sutured using titanium clips. RESULTS: Tumor size ranged from 2.0 to 4.5 cm (average 3.50 ± 0.84 cm). The operative time ranged from 60 to 130 min (average 83.33 ± 26.58 min). Blood loss was less than 20 mL and hospital stay ranged from 6 to 8 d (average 6.67 ± 0.82 d). The patients were allowed out of bed 12 h later. A stomach tube was inserted for 72 h after surgery, and a liquid diet was then taken. All cases had single tumors which were completely resected using the new-style LECS. No postoperative complications occurred. Pathology of all resected specimens showed GST: no cases of implantation or metastasis were found.CONCLUSION: New-style LECS for GSTs is a quick, optimized, fast recovery, safe and effective therapy.

Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors

AIM:To investigate primarily the prognostic value of Ki-67,as well as other parameters,in gastrointestinal stromal tumors(GISTs).METHODS:Ki-67,c-KIT,platelet-derived growth factor receptor-alpha(PDGFRα),smooth muscle actin(SMA),CD34,S100 were stained for immunohistochemistry which was performed on formalin-fixed,paraffinembeded sections on representative block from each case.Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells.Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively(weak,intermediate,strong) and for c-KIT type of reactivity was analyzed(cytoplasmic,membrane and "dot-like" staining).Immunoreactivity for SMA,CD34 and S100 were was evaluated as positive or negative antigen expression.Pathologic parameters investigated in this study included tumor size,cell type(pure spindle,pured epitheloid mixed spindle and epitheloid),mitotic count,hemorrhage,necrosis,mucosal ulceration.Clinical data included age,gender,primary tumor location and spread of disease.χ 2 test and Student's t-test were used for comparisons of baseline characteristics.The Cox's proportional hazard model was used for univariable and multivariable analyses.Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test.RESULTS:According to the stage of disease,there were 36 patients with localized disease,29 patients with initially localized disease but with its recurrence in the period of follow up,and finally,35 patients had metastatic disease from the very beginning of disease.Tumor originated most commonly in the stomach(41%),small intestine was the second most common location(36%).The mean size of primary tumors was 6.5 cm.The mean duration of follow-up was 60 mo.Multiple parameters were analyzed for their effect on overall survival,but no one reached statistical significance(P = 0.06).Analysis of time to progression/relapse in initially localized disease(univariate analysis),tumor size,mitotic count,Ki-67 and type of d-KIT distribution(cytoplasmic vs membrane/"dot-like") showed statistically significant correlation.In multivariate analysis in the group of patients with localized disease,there were only 2 parameters that have impact on relapse,Ki-67 and SMA(P < 0.0001 and P < 0.034,respectively).Furthermore,Ki-67 was analyzed in localized diseasevs localized with recurrence and metastatic disease.It was shown that there is a strict difference between these 2 groups of patients(median value was 2.5 for localized disease vs 10.0 for recurrent/metastatic disease,P < 0.0001).It was also shown that the cut-off value which is still statistically significant in terms of relapse on the level of 6%.The curves for survival on that cut-off level are significantly different(P < 0.04,Cox F).CONCLUSION:Ki-67 presents a significant prognostic factor for GIST recurrence which could be of great importance in evaluating malignant potential of disease.

Laparoscopic resection of gastric gastrointestinal stromal tumors presenting as left adrenal tumors

Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reported. We report two documented cases of gastric GISTs mimicking left adrenal tumors which were successfully treated with pure laparoscopic adrenalectomy and wedge resection of the stomach by excising the tumor from the stomach with serial fi ring of endoscopic gastrointestinal staplers. The surgical margins were clear, and the patients recovered smoothly. No adjuvant therapy with imatinib was prescribed. During the surveillance for 9 mo and 44 mo respectively, no tumor recurrence and metastasis were documented. Laparoscopic tumor excision, when adhering to the principles of surgical oncology, seems feasible and the prognosisis favorable for such tumors.

Laparoscopic management of gastric gastrointestinal stromal tumors: A retrospective 10-year single-center experience

AIM To determine the feasibility,safety,and oncological outcome of laparoscopic resection of gastric gastrointestinal stromal tumors(GISTs)based on favorable or unfavorable location.METHODS Our hospital database included 207 patients who underwent laparoscopic removal of gastric GISTs from January 2004 to September 2015.Patient demographics,clinical presentation,surgery,histopathology,postoperative course,and oncological outcomes were reviewed and analyzed.RESULTS Gastric GIST in favorable locations was present in81/207(39.1%)cases,and in unfavorable locations in 126/207(60.9%)cases.Overall mean tumor size was 3.28±1.82 cm.No conversions occurred,and complete R0 resection was achieved in 207(100%)cases.There were three incidences of iatrogenic tumor rupture.The feasibility and safety of laparoscopic surgery were comparable in both groups with no statistical difference between unfavorable and favorable location groups,respectively:for operative time:83.86±44.41 vs 80.77±36.46 min,P=0.627;conversion rate:0%vs 0%;estimated blood loss:27.74±45.2vs 29.59±41.18 m L,P=0.780;tumor rupture during surgery:0.90%vs 2.82%,P=0.322;or postoperative complications:3.74%vs 7.04%,P=0.325.The follow-up period recurrence rate was 1.89%with no significant differences between the two groups(3.03%vs 0%,P=0.447).Overall 5-year survival rate was98.76%and survival rates were similar between the two groups:98.99%vs 98.39%,P=0.623(unfavorable vs favorable,respectively).CONCLUSION The laparoscopic approach for gastric GISTs is safe and feasible with well-accepted oncological surgical outcomes.Strategies for laparoscopic resection should be selected according to the location and size of the tumor.Laparoscopic treatment of gastric GISTs in unfavorable locations should not be restricted in gastrointestinal centers.

Endoscopy dissection of small stromal tumors emerged from the muscularis propria in the upper gastrointestinal tract:Preliminary study

AIM:To investigate the feasibility and safety of the treatment of an upper gastrointestinal(GI) submucosal tumor with endoscopic submucosal dissection(ESD).METHODS:A total of 20 patients with esophageal and gastric submucosal tumors emerged from the muscular layer identified by endoscopic ultrasonography were collected from January 2009 to June 2010.Extramural or dumbbell-like lesions were excluded by an enhanced computerized tomography(CT) scan.All patients had intravenous anesthesia with propofol and then underwent the ESD procedure to resect these submucosal tumors.The incision was closed by clips as much as possible to decrease complications,such as bleeding or perforation,after resection of the tumor.All the specimens were collected and evaluated by hematoxylin,eosin and immunohistochemical staining,with antibodies against CD117,CD34,desmin,α-smooth muscle actin and vimentin to identify the characteristics of the tumors.Fletch's criteria was used to evaluate the risk of gastrointestinal stromal tumors(GISTs).All patients underwent a follow-up endoscopy at 3,6 and 12 mo and CT scan at 6 and 12 mo.RESULTS:The study group consisted of 5 men and 15 women aged 45-73 years,with a mean age of 60.2 years.Three tumors were located in the esophagus,9 in the gastric corpus,4 in the gastric fundus,3 lesions in the gastric antrum and 1 in the gastric angulus.Apart from the one case in the gastric angulus which was abandoned due to being deeply located in the serosa,94.7%(18/19) achieved complete gross dissection by ESD with operation duration of 60.52±30.32 min.The average maximum diameter of tumor was 14.8±7.6 mm,with a range of 6 to 30 mm,and another lesion was ligated by an endoscopic ligator after most of the lesion was dissected.After pathological and immunohistochemical analysis,12 tumors were identified as a GI stromal tumor and 6 were leiomyoma.Mitotic count of all 12 GIST lesions was fewer than 5 per 50 HPF and all lesions were at very low(9/12,75.0%) or low risk(3/12,25.0%) according to Fletch's criteria.Procedure complications mainly included perforation and GI bleeding;perforation occurred in 1 patient and conservative treatment succeeded by a suturing clip and no post-operative GI bleeding occurred.All patients were followed up for 6.5±1.8 mo(range,3-12 mo) by endoscopy and abdominal CT.Local recurrence and metastasis did not occur in any patient.CONCLUSION:ESD shows promise as a safe and feasible technique to resect esophageal and gastric submucosal tumors and the incidence of complications was very low.Clinical studies with more subjects and longer follow-up are needed to confirm its treatment value.

Prognostic angiogenic markers(endoglin, VEGF, CD31) and tumor cell proliferation(Ki67) for gastrointestinal stromal tumors

AIM: To evaluate the correlation between the immunoexpression of angiogenic markers [CD31, CD105 and vascular endothelial growth factor(VEGF)], proliferative index(Ki67), and prognosis of patients with gastrointestinal stromal tumors(GIST).METHODS: This is a retrospective study of 54 GIST cases. Medical records were searched to obtain the GIST patients' demographic and clinical data, and paraffin-embedded blocks of tumor samples were retrieved from the hospital archives to conduct a new immunohistochemical evaluation. The tumor samples of GIST patients were subject to immunohistochemical evaluation for endoglin(CD105), CD31, VEGF, and Ki67 expression. The CD105 and CD31 intratumoral microvascular density(IMVD) was measured using automated analysis. We determined the correlation between the immunoexpression of CD105, CD31, VEGF,Ki67 and prognosis. In addition, we conducted a cutoff analysis using the receiver-operating characteristic curve. VEGF positivity was classified as either null/weak or strong. Ki67 was evaluated using a cutoff of 5%positive cells. The prognosis was classified as good(patient alive without recurrence) or poor(patient with recurrence/death).RESULTS: The distribution of tumor sites among the54 analyzed samples was as follows: 27(50%) in the stomach, 20(37.1%) in the small intestine, 6(11.1%)in the colon, and 1(1.8%) in the esophagus. The size of the tumors ranged from 2 to 33 cm(median: 8cm); in 12 cases(22.2%), the tumor was below 5 cm at the largest diameter, but in 42 cases(77.7%), the tumor was larger than 5 cm. The means of CD105 and CD31 were significantly higher in the group with poor prognosis(P < 0.001). The cut-off values of CD105(>1.2%) and CD31(> 2.5%) in the receiver-operating characteristic curve were related to a poorer prognosis.Cases with a better prognosis showed significantly null/weak staining for VEGF(P < 0.001). Ki-67 expression of≥ 5% was strongly correlated with a worse prognosis(P< 0.001). In the multivariate analysis, CD105 was the variable that most strongly correlated with prognosis.CONCLUSION: The IMVD cutoff values for the angiogenic markers CD105 and CD31, may be prognostic factors for GIST, in addition to VEGF and Ki67.

Retrospective analysis of extra-gastrointestinal stromal tumors

AIM:To investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors(EGISTs)in South Korea.METHODS:A total of 51 patients with an EGIST were identified.The clinicopathologic features,including sex,age,location,tumor size,histology,mitotic rate,immunohistochemical features,genetic status and survival data,were analyzed.RESULTS:The median age was 55 years(range:29-80years),and male:female ratio was 1:1.04.The most common site was in the mesentery(n=15)followed by the retroperitoneum(n=13)and omentum(n=8).The median tumor size was 9.0 cm(range:2.6-30.0cm)and the median mitotic rate was 5.0/50HPF.(1/50-185/50).KIT was analyzed in 16,which revealed 10cases with wild-type KIT and 6 cases with an exon 11mutation.Among 51 patients,31 patients had undergone surgery,and 10 had unresectable disease and had taken palliative imatinib,which resulted in 22.7 mo of progression-free survival.Of the patients who had undergone surgery,18 did not take adjuvant imatinib,and 8 of these were categorized as"high risk"according to the risk criteria.However,the relapse-free survival was not different(P=0.157)between two groups.CONCLUSION:Because the biologic behaviors of GISTs differ according to the location of the tumor,a more stratified strategy is required for managing EGISTs including incorporation of molecular features.

Succinate dehydrogenase-deficient gastrointestinal stromal tumors

Most gastrointestinal stromal tumors(GISTs)are characterized by KIT or platelet-derived growth factor alpha(PDGFRA)activating mutations.However,there are still 10%-15%of GISTs lacking KIT and PDGFRA mutations,called wild-type GISTs(WT GISTs).Among these so-called WT GISTs,a small subset is associated with succinate dehydrogenase(SDH)deficiency,known as SDH-deficient GISTs.In addition,GISTs that occur in Carney triad and Carney-Stratakis syndromerepresent specific examples of SDH-deficient GISTs.SDH-deficient GISTs locate exclusively in the stomach,showing predilection for children and young adults with female preponderance.The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases.Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor(IGF1R)are common features of SDH-deficient GISTs.In WT GISTs without succinate dehydrogenase activity,upregulation of hypoxia-inducible factor 1αmay lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor(VEGFR).As a result,IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs.This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.