Intraductal papillary mucinous neoplasms and other pancreatic cystic lesions

Pancreatic cystic neoplasms are being increasingly recognized, even in the absence of symptoms, in large part, due to markedly improved imaging modalities such as magnetic resonance imaging （MRI）/magnetic resonance cholangio pancreatography （MRCP） and computer tomography （CT） scanning. During the past 2 decades, better imaging of these cystic lesions has resulted in definition of different types, including pancreatic intraductal papillary mucinous neoplasms （IPMN）. While IPMN represent only a distinct minority of all pancreatic cancers, they appear to be a relatively frequent neoplastic form of pancreatic cystic neoplasm. Moreover, IPMN have a much better outcome and prognosis compared to pancreatic ductal adenocarcinomas. Therefore, recognition of this entity is exceedingly important for the clinician involved in diagnosis and further evaluation of a potentially curable form of pancreatic cancer.     

Intraductal papillary mucinous neoplasms and other pancreatic cystic lesions

Pancreatic cystic neoplasms are being increasingly recognized, even in the absence of symptoms, in large part, due to markedly improved imaging modalities such as magnetic resonance imaging (MRI)/magnetic resonance cholangio pancreatography (MRCP) and computer tomography (CT) scanning. During the past 2 decades, better imaging of these cystic lesions has resulted in definition of different types, including pancreatic intraductal papillary mucinous neoplasms (IPMN). While IPMN represent only a distinct minority of all pancreatic cancers, they appear to be a relatively frequent neoplastic form of pancreatic cystic neoplasm. Moreover, IPMN have a much better outcome and prognosis compared to pancreatic ductal adenocarcinomas. Therefore, recognition of this entity is exceedingly important for the clinician involved in diagnosis and further evaluation of a potentially curable form of pancreatic cancer.     

Endoscopic ultrasound and computer tomography are inaccurate methods of classifying cystic pancreatic lesions

BACKGROUND: Despite advances in imaging modalities, preoperative diagnosis of pancreatic cystic lesions remains difficult. AIM: To assess the accuracy of endoscopic ultrasound and computer tomography to preoperatively distinguish benign from potentially malignant and malignant pancreatic cystic lesions. METHODS: Photograph series obtained from endoscopic ultrasound examinations of 66 patients with cystic pancreatic lesions were blindly reviewed by three endoscopic ultrasonographers. Forty-one of those 66 patients also underwent a computer tomography scan at our institution, which was blindly reviewed by a single radiologist. Computer tomography and endoscopic ultrasound classification into benign and malignant and potentially malignant pancreatic cystic lesions was correlated with the final diagnosis, which was established by surgical pathology (n = 43), diagnostic fine needle aspiration (n = 13) or follow-up imaging (n = 10). Interobserver agreement was measured using kappa statistics. RESULTS: Endoscopic ultrasound classification by the three examiners into benign versus malignant or potentially malignant cystic lesions was correct in 65-67%. Interobserver agreement was 50%. Kappa values for pairs of endoscopic ultrasound examiners were 0.16, 0.43 and 0.53. Computer tomography classification was correct in 71% and in agreement with the endoscopic ultrasound classification in 56-61% (kappa 0.12 to 0.27). CONCLUSIONS: Endoscopic ultrasound and computer tomography cannot accurately distinguish between benign pancreatic cystic lesions and malignant or potentially malignant ones. There is poor-to-modest interobserver agreement in classifying these lesions.     

Endosonography in the diagnosis and management of pancreatic cysts

Rapid advances in radiologic technology and increased cross-sectional imaging have led to a sharp rise in incidental discoveries of pancreatic cystic lesions. These cystic lesions include non-neoplastic cysts with no risk of malignancy, neoplastic non-mucinous serous cystadenomas with little or no risk of malignancy, as well as neoplastic mucinous cysts and solid pseudopapillary neoplasms both with varying riskof malignancy. Accurate diagnosis is imperative as management is guided by symptoms and risk of malignancy. Endoscopic ultrasound(EUS) allows high resolution evaluation of cyst morphology and precise guidance for fine needle aspiration(FNA) of cyst fluid for cytological, chemical and molecular analysis. Initially, clinical evaluation and radiologic imaging, preferably with magnetic resonance imaging of the pancreas and magnetic resonance cholangiopancreatography, are performed. In asymptomatic patients where diagnosis is unclear and malignant risk is indeterminate, EUSFNA should be used to confirm the presence or absence of high-risk features, differentiate mucinous from non-mucinous lesions, and diagnose malignancy. After analyzing the cyst fluid for viscosity, cyst fluid carcinoembryonic antigen, amylase, and cyst wall cytology should be obtained. DNA analysis may add useful information in diagnosing mucinous cysts when the previous studies are indeterminate. New molecular biomarkers are being investigated to improve diagnostic capabilities and management decisions in these challenging cystic lesions. Current guidelines recommend surgical pancreatic resection as the standard of care for symptomatic cysts and those with high-risk features associated with malignancy. EUSguided cyst ablation is a promising minimally invasive, relatively low-risk alternative to both surgery and surveillance.     

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic cysts by combined cytopathology and cystic content analysis

Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUS-guided FNA and the cytological diagnosis for pancreatic cysts.     

Cystic neoplasms of the pancreas： A diagnostic challenge

Cystic neoplasms of the pancreas are increasingly recognized due to the expanding use and improved sensitivity of cross-sectional abdominal imaging. Major advances in the last decade have led to an improved understanding of the various types of cystic lesions and their biologic behavior. Despite significant improvements in imaging technology and the advent of endoscopic-ultrasound （EUS）-guided fine- needle aspiration, the diagnosis and management of pancreatic cystic lesions remains a significant clinical challenge. The first diagnostic step is to differentiate between pancreatic pseudocyst and cystic neoplasm. If a pseudocyst has been effectively excluded, the cornerstone issue is then to determine the malignant potential of the pancreatic cystic neoplasm. In the majority of cases, the correct diagnosis and successful management is based not on a single test but on incorporating data from various sources including patient history, radiologic studies, endoscopic evaluation, and cyst fluid analysis. This review will focus on describing the various types of cystic neoplasms of the pancreas, their malignant potential, and will provide the clinician with a comprehensive diagnostic approach.     

Endoscopic ultrasound in the diagnosis and treatment of pancreatic disease

Endoscopic ultrasound(EUS)is an important part of modern gastrointestinal endoscopy and now has an integral role in the diagnostic evaluation of pancreatic diseases.Furthermore,as EUS technology has advanced,it has increasingly become a therapeutic procedure,and the prospect of multiple applications of interventional EUS for the pancreas is truly on the near horizon.However,this review focuses on the established diagnostic and therapeutic roles of EUS that are used in current clinical practice.In particular,the diagnostic evaluation of acute pancreatitis,chronic pancreatitis,cystic pancreatic lesions and solid masses of the pancreas are discussed.The newer enhanced imaging modalities of elastography and contrast enhancement are evaluated in this context.The main therapeutic aspects of pancreatic EUS are then considered,namely celiac plexus block and celiac plexus neurolysis for pain control in chronic pancreatitis and pancreas cancer,and EUS-guided drainage of pancreatic fluid collections.     

Palliative endoscopic ultrasound-guided drainage of a malignant pancreatic cyst causing gastric outlet obstruction.

BACKGROUND: Endoscopic ultrasound (EUS)-guided drainage of pancreatic pseudocysts has been well described but it is not an established therapy for malignant pancreatic cystic neoplasms. We report the first EUS-guided cystogastrostomy for the palliative treatment of a cystic pancreatic adenocarcinoma. CASE REPORT: We describe a 70-year-old male with a nonresectable cystic pancreatic adenocarcinoma causing partial gastric outlet obstruction treated successfully with palliative EUS-guided cystogastrostomy stent placement. The diagnosis was confirmed by EUS-guided fine needle aspiration. Computerized tomography (CT) and EUS staging revealed vascular invasion precluding the patient from surgical resection. Cystogastrostomy was performed entirely under EUS guidance utilizing a 10-Fr double pigtail stent. After cystogastrostomy stent placement, the patient developed dramatic symptomatic improvement of gastric outlet obstructive symptoms, although subsequent imaging did not reveal complete collapse of the cystic structure. CONCLUSION: EUS-guided cystogastrostomy can be considered in the palliative treatment of nonresectable pancreatic cystic neoplasms. Cyst decompression may result in significant symptomatic improvement, although the architecture of malignant cysts may prevent complete resolution.     

Últimos avances sobre los tumores pancreáticos

Pancreatic cancer (PC) continues to have a very poor prognosis. New epidemiological trials suggest that statins could play a protective role in smokers, while HbsAg-positive hepatitis B virus could be a risk factor. Endoscopic ultrasound (EUS) is the main diagnostic tool for PC, and new technologies associated with this technique have emerged, such as quantitative elastography, intravenous contrasts or, more recently, LASER confocal endomicroscopy. New markers in urine or pancreatic juice have appeared to distinguish between PC and chronic pancreatitis. The role of the “on site” cytopathologist to increase the diagnostic yield of EUS-guided pancreatic sampling is completely supported by new prospective trials and some multicenter studies have been reported that compare the standard cytologic needles with the new procore-histology needles. Regarding cystic pancreatic tumors, most studies have aimed to validate the 2012 Sendai international guidelines and to ascertain predictive factors of malignancy in cystic lesions, mainly intraductal papillary mucinous neoplasm (IPMN). The role of intracystic CEA levels in determining malignancy is challenged. From a therapeutic point of view, EUS-guided radiofrequency ablation of cystic and solid lesions has emerged as a feasible and safe procedure in specific circumstances.     

EUS-Guided Antitumor Therapy for Pancreatic Tumors

Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.     

Diagnostic Concordance and Preoperative Risk Factors for Malignancy in Pancreatic Mucinous Cystic Neoplasms

Background/AimsAs pancreatic mucinous cystic neoplasms (MCNs) are considered premalignant lesions, the current guidelines recommend their surgical resection. We aimed to investigate the concordance between preoperative and postoperative diagnoses and evaluate preoperative clinical parameters that could predict the malignant potential of MCNs.MethodsPatients who underwent surgical resection at Samsung Medical Center for pancreatic cystic lesions and whose pathology was confirmed to be MCN, between July 2000 and December 2017, were retrospectively analyzed.ResultsAmong a total of 132 patients 99 (75%) were diagnosed with MCN preoperatively. The most discordant preoperative diagnosis was an indeterminate pancreatic cyst. The proportion of male patients was higher (24.2% vs 7.1%, p=0.05) in the diagnosis-discordance group and the presence of worrisome features in radiologic imaging studies, such as wall thickening/enhancement (12.1% vs 37.4%, p=0.02) or solid component/mural nodule (3.0% vs 27.3%, p=0.02), was lower in the diagnosis-discordance group. The presence of symptoms (57.7% vs 34.9%, p=0.02), tumor size greater than 4 cm (80.8% vs 55.7%, p=0.04), and radiologic presence of a solid component/mural nodule (42.3% vs 16.0%, p=0.01) or duct dilatation (19.2% vs 6.6%, p=0.01) were significantly associated with malignant MCNs.ConclusionsIn our study, the overall diagnostic concordance rate was confirmed to be 75%, and our findings suggest that MCNs have a low malignancy potential when they are less than 4 cm in size, are asymptomatic and lack worrisome features on preoperative images.     

Laparoscopic fenestration of pancreatic serous cystadenoma:Minimally invasive approach for symptomatic benign disease

Serous cystadenoma(SC) is a benign pancreatic cystic tumor. Surgical resection is recommended for symptomatic forms, but laparoscopic fenestration of large symptomatic macrocystic SC was not yet described in the literature. In this study, 3 female patients underwent laparoscopic fenestration for macrocystic SC(12-14 cm). Diagnosis was established via magnetic resonance imaging and endoscopic ultrasound, with intra-cystic dosage of tumors markers(ACE and CA19-9) in 2 patients. All patients were symptomatic and operated on 15-60 mo after diagnosis.Radiological evaluation showed constant cyst growth.Patients were informed about this new surgical modality that can avoid pancreatic resection. The mean operative time was 103 min(70-150 min) with one conversion.The post-operative course was marked by a grade A pancreatic fistula in one patient and was uneventful in the other two. The hospital stay was 3, 10, and 18 d, respectively. The diagnosis of macrocystic SC was histologically-confirmed in all cases. At the last followup(13-26 mo), all patients were symptom-free, and radiological evaluation showed complete disappearance of the cyst. Laparoscopic fenestration, as opposed to resection, should be considered for large symptomatic macrocystic SC, thereby avoiding pancreatic resection morbidity and mortality.     

Utility of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration for the diagnosis and management of pancreatic cystic lesions: Differences between the guidelines

Recent advances and frequent use of cross-sectional imaging studies have increased opportunities for incidental diagnoses of pancreatic cystic lesions (PCL). In the management of PCL, distinguishing between mucinous versus non-mucinous and malignant versus benign cysts is important to diagnose pancreatic cancer in its early stage. For this reason, there have been several guidelines to manage PCL. Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) play important roles in the guidelines, although there are some differences in their roles. In this review, we aimed to evaluate the current status of EUS and EUS-FNA in the management of PCL and the status of these procedures in the guidelines.     

Endoscopic ultrasound-guided injective ablative treatment of pancreatic cystic neoplasms

With the development of cross-sectional imaging modalities and the increasing attention being paid to physical examinations, the prevalence of pancreatic cystic neoplasms(PCNs) has increased. PCNs comprise a broad differential spectrum with some PCNs having low or no malignant potential and others having high malignant potential. The morbidity and mortality rates related to major pancreatic surgical resection are high. Long-term surveillance may not only increase the financial burden and psychological stress for patients but also result in a missed malignancy. Minimally invasive endoscopic ultrasound(EUS)-guided ethanol ablation was first reported in 2005. Several other agents, such as paclitaxel, lauromacrogol, and gemcitabine, were reported to be effective and safe for the treatment of PCNs. These ablative agents are injected through a needle inserted into the cyst via transgastric or transduodenal puncture. This treatment method has been substantially developed in the last 15 years and is regarded as a promising treatment to replace surgical resection for PCNs. While several reviews of EUS-guided ablation have been published, no systematic review has evaluated this method from patient preparation to follow-up in detail. In the present review, we systematically describe EUS-guided injective ablation with regard to the indications, contraindications, preoperative treatment, endoscopic procedure, postoperative care and follow-up, evaluation method, treatment efficiency, safety profile, tips and tricks, and current controversies and perspectives.     

Current status on the diagnosis and management of pancreatic cysts in the Asia-Pacific region: role of endoscopic ultrasound

Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) play increasingly prominent roles in the diagnosis and management of pancreatic cysts. The Asian Consortium of Endoscopic Ultrasound was recently formed to conduct collaborative research in this area. This is a review of literature on true pancreatic cysts. Due to the lack of systematic studies, there are no robust data on the true incidence of pancreatic cystic lesions in Asia and any change in over the recent decades. Certain EUS morphological features have been used to predict particular types of pancreatic cysts. Pancreatic cyst fluid viscosity, cytology, pancreatic enzymes, and tumor markers, in particular carcinoembryonic antigen, can aid in the diagnosis of pancreatic cysts. Hemorrhage and infection are the most common complications of EUS-FNA of pancreatic cysts. Pancreatic cysts can either be observed or resected depending on the benign or malignant nature, or malignant potential of the lesions. Guidelines from an international consensus did not require positive cytological findings to be present in their recommendation for resection, which included all mucinous cystic neoplasms, all main-duct intraductal papillary mucinous neoplasms (IPMN), all mixed IPMN, symptomatic side-branch IPMN, and side-branch IPMN larger than 3 cm. In patients with poor surgical risks, EUS-guided cyst ablation of mucinous pancreatic cysts is an alternative. As long-term prospective data on pancreatic cysts are still not available in Asia, management strategies are largely based on risk stratification by surgical risk and malignant potential. Gene expression profiling of pancreatic cyst fluid and confocal laser endomicroscopic examination of pancreatic cysts are novel techniques currently being studied.     

Does next-generation sequencing of cyst fluid improve management of pancreatic cystic neoplasms?

Pancreatic cystic lesions represent a heterogeneous group of diseases ranging from benign to malignant lesions. They are increasingly being detected due to the widespread use of cross-sectional imaging. Their management is a challenge because it is often not possible to reliably discriminate between malignant and nonmalignant lesions using current imaging technology. Next-generation sequencing (NGS) has the ability of both whole genome and targeted sequencing at a low cost and from a limited amount of DNA. NGS of cyst fluid aspired by endoscopic ultrasonography-guided fine-needle aspiration provides a valuable tool in biomarker research and may in the future help improve diagnosis and management of pancreatic cystic lesions.     

内镜超声引导下细针穿刺对胰腺占位病变的诊断价值

目的 通过超声内镜结合细针穿刺活检确定胰腺占位病变的性质，并评价该法对胰腺病变的诊断价值。方法 对经CT、MRI、体表腹部超声及内镜超声发现的23例胰腺局限性占位病变进行内镜超声检查，以明确病变大小、形态、位置，并观察有无淋巴结转移。在内镜超声引导下对病变行细针穿刺活检。结果 23例患者中，21例得到了充足的细胞量，15例得到组织块，12例最终确定为胰腺肿瘤的患者，经组织细胞学检查10例为阳性（其中胰腺癌8例；胰腺囊腺瘤癌1例；无功能神经内分泌肿瘤1例），敏感性为83％，特异性为100％。全部结果经手术（16例）及临床随访（7例）证实。无1例出现不良反应。结论 超声内镜结合细针穿刺是诊断胰腺病变安全、有效的方法。     

Endoscopy-guided ablation of pancreatic lesions:Technical possibilities and clinical outlook

Endoscopic ultrasound(EUS) and endoscopic retrograde cholangiopancreatography(ERCP)-guided ablation procedures are emerging as a minimally invasive therapeutic alternative to radiological and surgical treatments for locally advanced pancreatic cancer(LAPC), pancreatic neuroendocrine tumours(PNETs), and pancreatic cystic lesions(PCLs). The advantages of treatment under endoscopic control are the real-time imaging guidance and the possibility to reach a deep target like the pancreas. Currently, radiofrequency probes specifically designed for ERCP or EUS ablation are available as wel as hybrid cryotherm probe combining radiofrequency with cryotechnology. To date, many reports and case series have confirmed the safety and feasibility of that kind of ablation technique in the pancreatic setting.Moreover, EUS-guided fine-needle injection is emerging as a method to deliver ablative and anti-tumoral agents inside the tumuor. Ethanol injection has been proposed mostly for the treatment of PCLs and for symptomatic functioning PNETs, and the use of gemcitabine and paclitaxel is also interesting in this setting. EUS-guided injection of chemical or biological agents including mixed lymphocyte culture, oncolytic viruses, and immature dendritic cells has been investigated for the treatment of LAPC. Data on the long-term efficacy of these approaches,and large prospective randomized studies are needed to confirm the real clinical benefits of these techniques for the management of pancreatic lesions.     

Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions

BackgroundSemiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA.Patients and methodsThis single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS-FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome.Results91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01–43.94 95% CI vs 44.00; 32.42–55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison.ConclusionSemiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging.     

Methods and outcomes of screening for pancreatic adenocarcinoma in high-risk individuals

Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasia, for which secondary prevention (i.e., screening) is advisable for high-risk individuals with “familiar pancreatic cancer” and with other specific genetic syndromes (Peutz-Jeghers, p16, BRCA2, PALB and mismatch repair gene mutation carriers). There is limited evidence regarding the accuracy of screening tests, their acceptability, costs and availability, and agreement on whom to treat. Successful target of screening are small resectable PDAC, intraductal papillary mucinous neoplasms with high-grade dysplasia and advanced pancreatic intraepithelial neoplasia. Both magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are employed for screening, and the overall yield for pre-malignant or malignant pancreatic lesions is of about 20% with EUS and 14% with MRI/magnetic resonance colangiopancreatography. EUS performs better for solid and MRI for cystic lesions. However, only 2% of these detected lesions can be considered a successful target, and there are insufficient data demonstrating that resection of benign or low grade lesions improves survival. Many patients in the published studies therefore seemed to have received an overtreatment by undergoing surgery. It is crucial to better stratify the risk of malignancy individually, and to better define optimal screening intervals and methods either with computerized tools or molecular biomarkers, possibly in large multicentre studies. At the moment, screening should be carefully performed within research protocols at experienced centres, offering involved individuals medical and psychological advice.