| Objectives: Through the retrospective study of gastrointestinal stromal tumor(GIST)in Renji Hospital,Shanghai Jiaotong University School of Medicine to evaluate the prognostic value and correlation with imatinib-resistance of the clinical pathological and genetic characteristics of GIST patients.To discuss and analyze the key points of preoperative diagnosis of gastrointestinal stromal tumors.Investigate the role of hedgehog(Hh)signaling pathway in the prognosis of gastrointestinal stromal tumors and imatinib resistance by means of expression plasmids and cell assays.Methods:(1)To evaluated the prognostic value and correlation with imatinib-resistance of the clinical pathological characteristics of 1063 GIST patients from Department of General Surgery and Gastroenterology,Renji Hospital,Shanghai Jiaotong University School of Medicine from November 1997 to December 2016.(2)To evaluated the prognostic value and correlation with imatinib-resistance of the genetics characteristics of 514 GIST patients received gene mutation detection.(3)To discuss the key points of preoperative diagnosis of gastrointestinal stromal tumors by analyzing 49 misdiagnosed patients received multidisciplinary team(MDT)discussion of Gastrointestinal Surgery of Renji Hospital,Shanghai Jiaotong University School of Medicine from July 2015 to February 2017.(4)To investigate the role of Hh signaling pathway and related proteins in the prognosis of gastrointestinal stromal tumors and imatinib resistance by means of expression plasmids and cell assays by tissue microarrays,PCR and cell experiments.Result:(1)In the 1063 cases of GIST cases,637 cases(59.9%)were primary located in stomach,255 cases(24.0%)in small intestine,44 cases(4.1%)in duodenum,37 cases(3.5%)in rectum,18 cases(1.7%)in colon and 72 cases in other parts(including mesangial,peritoneum,omentum,diaphragm,etc.).612 cases(57.6%)underwent classical open surgery(including 25 cases of resection of rectal tumor),240 cases(22.6%)underwent laparoscopic surgery,162 cases(15.2%)underwent endoscopic resection,and 49cases(4.6%)underwent laparoscopic combined endoscopic surgery.According to the NIH classification,299 cases(18.7%)were classified as very low risk arm,383 cases(36.0%)as low risk,145 cases(13.7%)as intermediate risk,and 336 cases(31.6%)as high risk.The 1-year,3-year and 5-year percentage of disease-free survival(DFS)of 791 GIST patients was98.3%,89.7%,82.1%,and the overall survival(OS)were 98.0% and 93.9%.89.7%.The 5-year DFS of very low risk,low risk,intermediate risk and high risk arm were 100.0%,98.0%,93.8%,57.4% and OS were 100.0%,98.5%,94.4%,78.5%.(2)In the 514 cases of GIST cases received gene mutation test,276 cases(53.7%)were primary located in stomach,161cases(31.3%)in duodenum and small intestine,14 cases(4.1%)in colon and rectum and 63 cases(12.3%)in other parts.According to the NIH classification,26 cases(5.1%)were classified as very low risk arm,150 cases(29.2%)as low risk,111 cases(21.6%)as intermediate risk,and 227 cases(44.2%)as high risk.In 514 cases,454 cases were detected c-kit gene mutation,27 cases PDGFRA gene mutation and 33 wild-type cases.In 454 c-kit mutation cases,393 were detected exon 11 mutation,52 cases in exon 9,7 cases in exon 17 and 2 cases in exon 17.In 27 PDGFRA mutation cases,18 cases were detected exon mutation 18 mutation and 6 cases in exon 12.In the exon 11 of c-kit gene mutation,the deletion mutation was 211 cases(53.7%)(211/393),point mutation was 180 cases and 35 cases was duplication mutations,42 cases had two mutation type at the same time.The non-11 exon of c-kit gene mutation was more detected than exon 11 mutation.The size of tumor without point and duplication mutation was smaller than point mutation.The mitotic count is higher in deletion mutation than others.The prognosis of PDGFRA mutation was relatively good and the wild type had the worst prognosis.The prognosis of patients with deletion mutation was worse.single codon involvement in the case of c-kit 11 deletion mutation showed a better prognosis.There was no significant prognostic difference of different mutation type(point mutations/deletions)involving single codons.In intermediate and high risk patients,deletion mutations and multiple codons involced cases got worse prognosis.Imatinib adjuvant therapy can improve postoperative DFS.Mutiple codons involved cases were associated with a worse prognosis and stronger imatinib resistance.(3)It is difficult on preoperative diagnosis and differential diagnosis of gastrointestinal stromal tumors,especially on small size(<5cm)of GISTs.The combination of ultrasonoendoscopy,contrast-enhanced ultrasound,enhanced CT and enhanced MRI with DWI examination,and discussion by multi-disciplinary doctors can provide a most suitable diagnosis for GIST.(4)The expression of Gli1?3 and SMO in high-risk GIST was significantly higher than that in lower risk ones,while the expression of Ptch1 was significantly decreased.The higher expression of PTCH1 lower expression of SMO predicted better prognosis.In the GIST-T1imatinib-resistant cell line,SMO expression was higher than that of non-resistant strains.The resistance of GIST-T1-resistant cells to imatinib was reduced after SMO interference in GIST-T1 resistant strains.Conclusion:(1)The tumor primary site,tumor size,mitotic count and the NIH classification were the independent influencing factors of long-term survival and disease-free survival in GIST patients.IM adjuvant therapy can improve DFS and OS in GIST patients.(2)Mutation type(deletion/deletion mutation)and codon involved number(single codon/multiple codon)were statistically different in prognosis.The prognosis of GIST with point mutation was better than that of deletion mutation may be due to the fact that 95.6%(172/180)of the point mutations involve a single codon and 73.0%(154/211)of the deletion mutations involve multiple codons;According to NIH classification,single codon involvement in the risk of intermediate cases is better than multiple codons involved in low-risk cases,suggesting that the current classification of GIST risk is not perfect,the number of mutations involving the number of codons associated with the risk of GIST,which could play an important role in judging the risk grading of GIST;The number of codons involved in gene mutation could predict the sensitivity of targeted therapy with imatinib.(3)The combination of ultrasonoendoscopy,contrast-enhanced ultrasound,enhanced CT and enhanced MRI with DWI examination,and discussion by multi-disciplinary doctors can provide a most suitable diagnosis for GIST.(4)The higher the expression of PTCH1,the lower the expression of SMO,the better the prognosis of GIST.The expression level of SMO was positively correlated with the resistance of imatinib to GIST. |
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