Application Of Endoscopic Ultrasound-guided Fine Needle Aspiration In Diagnosis And Treatment Of Pancreatic Cystic Neoplasm

Pancreatic cystic neoplasm(PCNs)represent a wide clinicopathologic spectrum.Diverse biological characters presented in different pathologic types of PCNs.Intraductal papillary mucinous neoplasm(IPMNs)and mucinous cystadenomas(MCNs)represent precursor lesions to invasive adenocarcinoma.Cystic pancreatic neuroendocrine tumor,cystic ductal adenocarcinoma,cystic adenosquamous carcinoma and solid pseudopapillary neoplasm(SPNs)are acknowledged as invasive adenocarcinoma.Due to the malignancy potential of PCNs,surgical resection was recommended for all PCNs in the past.However,due to the increasing morbidity of PCNs,low malignancy rate of PCNs and high complication rate of pancreatic surgeries,thus,the accurate surgical opportunity choice is crucial for management of PCNs.Surgical resection for advanced pancreatic cystic neoplasm(adenocarcinoma and high-grade dysplasia,A-PCNs)is considered as the ideal indication.However,diagnosing the A-PCNs patients before surgery remains a difficulty.Endoscopic ultrasound(EUS)has the ability of scanning the pancreas dynamically,the fine structure of the pancreas and the surrounding tissues structure are clearly displayed by high frequency ultrasound.EUS is considered superior to Computed Tomography(CT)and Magnetic Resonance Imaging(MRI)in sensitive,specificity,positive predictive value,negative predictive value and diagnostic accuracy in classifying PCNs.Endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)can increase the diagnostic accuracy compare with EUS alone through cyst fluid analysis.The American Gastroenterological Association(AGA)published guidelines for management of asymptomatic pancreatic cystic neoplasm(PCNs)in 2015.The guidelines emphasized the importance of endoscopic ultrasonography-guided fine needle aspiration(EUS-FNA).The accuracy of AGA guidelines detecting advanced neoplasm has been suspected recently.The rate of missing A-PCNs will increase result in adopting the guidelines.However,the diagnose value of detecting MNs has not evaluated yet.Liquid-based cytology is now most widely used for differential A-PCNs and non A-PCNs.However,the sensitive in differential A-PCNs for liquid-based cytology was only about 48%,although the specificity is favorable.Cyst fluid Carcino-embryonic antigen(CEA)level was reported as an effective standard in differential mucinous and non-mucinous cystic neoplasm.But for differential A-PCNs and non A-PCNs,the standard was not established though many relevantly studies have been published.Multicenter,large sample size and prospective studies are excepted.In consideration of dissatisfactory abilities for the 2 methods in predicting A-PCNs,combining 2 methods together seems promising.Further studies are needed.Endoscopic ultrasound-guided fine needle aspiration in the treatment of PCNs has developed fast recently.Endoscopic ultrasound-guided ethanol ablation(EUS-EA)is one of the most widely applied methods in clinical practice,the procedure process is similar with EUS-FNA.Ethanol are injected through the channel of puncture needle and proteins in cyst wall cell are degenerated.Comparing with surgical resection,EUS-EA is less invasive and undergoing a quick recovery which has a great significant in PCNs treatment.Many studies about EUS-EA have been published.However,the effectiveness of EUS-EA has been doubted though the safety has been proved,which restricted the application in clinical practice.Further more,2 punctures are needed as current clinical approach recommended.EUS-EA should follow EUS-FNA cyst fluid analysis to determine the therapy is suitable or not.Combining EUS-FNA and EUS-EA in one puncture has not been reported,and mucinous patient choice is still not in conclusion.Adopting high risk factors evaluation in patients choice may be suitable.The accuracy of high risk factors evaluation need to be evaluated.The study aims to assess the value AGA guidelines in detecting MNs and reevaluate the value of cyst fluid CEA level and cytology examination obtained by EUS-FNA in predicting A-PCNs and to evaluate technical efficacy,feasibility and safety of EUS-EA for PCNs.The study was divided into 3 parts:Part1 : Evaluating value of American Gastroenterological Association Guidelines on the diagnosis and management of asymptomatic pancreatic cystic neoplasm in detecting mucinous neoplasmObjective:The study aimed to assess the accuracy of the AGA guideline and alternative approach in detecting mucinous neoplasm(MNs).Methods:A total of 124 PCNs patients were included.All patients were evaluated by EUS-FNA and cyst fluid CEA study.For each patient,clinical features,EUS findings(size of cysts,solid component in cysts,diameter of main pancreatic duct,septae,cyst location and locularity of cyst),cyst fluid CEA level were reviewed.Cyst fluid CEA level>192ng/ml are determined as MNs.Univariate,multivariate analysis and ROC curve analysis were used for data analysis.Results:The size of cysts had significant difference between 2 groups(P=0.032).Based on multivariate analysis,size of cysts>1.5cm(odds ratio [OR],0.134,95% confidence interval [CI],0.014– 0.948)predicted MNs.The sensitivity,specificity,positive predictive value,negative predictive value and accuracy of AGA guidelines detecting MNs were 20.5%,73.8%,30%,62.8% and 54.8%,while the alternative approach were 43.2%,61.3%,38%,66.2% and 54.8%,respectively.The AGA approach missed(35/44[79.5%])MNs while(25/44[56.8%])for alternative approach.The ROC curve showed alternative approach had similar diagnostic efficiency with AGA guidelines approach(P>0.05),but alternative approach missed less MNs than AGA approach(P=0.022).Conclusions:The AGA guidelines need improvements in detecting MNs.The risk of missing MNs with alternative approach was lower than AGA approach though they had similar diagnostic efficiency,further study is needed.Part2:Evaluating value of endosonography-guided fine needle aspiration cyst fluid carcinoembryonic antigen concentration,cytology and combining 2 methods in predicting advanced pancreatic cystic neoplasms.Objective:To assess the value of CEA level and cytology examination obtained by EUS-FNA in predicting the advanced neoplasm.Methods:The data of patients with PCN who underwent surgical resction after EUS-FNA in Changhai Hospital,Second Military Medical University(Shanghai,China)from June 2006 to June 2017 were collected and analyzed.78 patients were included.For each patient,demographic information,EUS features,cytopathology results,carcinoembryonic antigen(CEA)values and pathologic outcomes were recorded.Sensitive,specificity,positive predictive value,negative predictive value and diagnostic accuracy were applied to assess the value of cytology and cyst fluid CEA level predict A-PCNs.Student’s T test were applied to compare the cyst fluid CEA level between A-PCNs and non A-PCNs groups.Receiver operating characteristic(ROC)curve were applied to identified the CEA cutoff level for predicting A-PCNs.Result:Of the 78 PCNs confirmed by surgical pathology,32 were A-PCNs.There were significant difference between A-PCNs groups and non A-PCNS groups(P=0.002).Sensitive,specificity,positive predictive value,negative predictive value and diagnostic accuracy for liquid-based cytology differential A-PCNs from non A-PCNs were 48.1%,90.9%,81.3%,68.2%和 55.1%.CEA of > 418.9 ng/mL was able to predict A-PCNs(P = 0.049)with sensitivity of 85.7%,specificity of 73.1%,PPV of 46.2%,NPV of 95% and accuracy of 75.8% and its under ROC curve area was 0.863.The sensitive,specificity,positive predictive value,negative predictive value and diagnostic accuracy in differential A-PCNs from non A-PCNs were 100%,73.1%,56.3%,100% and 80% when combining 2 methods together。Conclusion:Cyst fluid CEA level and liquid-based cytology obtained by EUS-FNA are useful for predicting the A-PCNs.Combining 2 methods together could improve sensitive and accuracy in predicting A-PCNsPart3:The preliminary efficacy and safety evaluation of Endoscopic ultrasound-guided ethanol ablation for pancreatic cystic neoplasms.Objective:To evaluate technical efficacy,feasibility and safety of EUS-EA for PCNs and explore the possibility of combining EUS-FNA and EUS-EA.Methods:A clinical date of 11 patients with PCNs in Changhai hospital from July 2013 to August 2017 were retrospectively studied.The demography data,EUS features,adverse events and follow-up data were recorded.Treatment response was classified as complete resolution(CR),partial resolution(PR),stable disease(SD)and progressive disease(PD),with disappear,decrease size and persistent size and increase size of the original cysts.The high risk factors in guidelines published by American Gastroenterological Association(AGA)were retrospectively applied to determine whether the cyst is capable for combining EUS-FNA and EUS-EA.If the final cyst fluid analysis identified the cyst was suspected of MNs,the combining EUS-FNA and EUS-EA was considered as significant.Results:The median largest diameter of the cyst was 2.80±1.49 cm.The median fellow-up time was 4.0 months(3-12 months).Based on cyst fluid analysis there were 4 mucinous cystic neoplasms,6 serous cystic neoplasms,and 1 indeterminate cyst.There were total 13 operations performed,and the operation successful rate was 100%.No severe complication occured.The overall treatment response was as follows: complete resolution in 5(45.5%),partial resolution in 5(45.5%),no resolution in 1(9%).Among 4 MCNs,3 with cyst size >3cm and had mural nodules.The sensitive,specificity,positive predictive value,negative predictive value and accuracy of adopting high risk evaluation in choosing patients who were capable for combining EUS-FNA and EUS-EA were 75%,62.5%,50%,83.3% and 72.7%.Conclusion:EUS-EA was safe and effective in the treatment of patient with PCN.EUS-FNA combined with EUS-EA is feasible.Further studies with larger samples and longer follow-up are excepted.According to the study above,conclusions were drew as fellow:1.The improvement and supplement in AGA guidelines will decrease the missed diagnosis rate of MNs.2.EUS-FNA and cyst fluid analysis are helpful in predicting A-PCNs,combining 2 methods could improve the sensitive and accuracy in detecting MNs.3.Standard procedures for EUS-EA is the goal for further research which should based on multicenter,large sample size and prospective studies.Combining EUS-FNA and EUS-EA may be feasible.