Endosonographic diagnosis of advanced neoplasia in intraductal papillary mucinous neoplasms

Pancreatic cancer has a high mortality rate with minimal proven interventions.Intraductal Papillary Mucinous Neoplasms(IPMNs) are known precursor lesions for pancreatic cancer. Identification of pancreatic cysts has improved from advances in abdominal imaging. Despite multiple revisions of the international consensus recommendations and various guidelines by other major societies,successful risk stratification of the malignant potential of mucinous pancreatic cysts remains challenging. Specifically, detection and accurate classification of advanced neoplasia(high-grade dysplasia and/or adenocarcinoma) in IPMNs is suboptimal with current diagnostic strategies. Development of interventional techniques utilizing endoscopic ultrasound include-through-the-needle microforceps biopsy, next-generation or whole genome molecular analysis of cyst fluid, and needle-based confocal laser endomicroscopy. These techniques suffer from a series of limitations in technical success, diagnostic yield, and clinical feasibility, but a combination approach may offer a solution that optimizes their cyst evaluation and risk stratification. Assessment and comparison of these techniques is restricted by lack of adequate surgical specimens for testing of diagnostic accuracy, resulting in a possible sample bias. Additional large-scale multicenter studies are needed to accumulate evidence for the utility and feasibility of their translation into clinical practice. Great strides have been made in pancreatic cyst evaluation, but further research is required to improve diagnostic accuracy and clinical management of IPMNs.     

Diagnosis of intraductal papillary mucinous neoplasm using endoscopic ultrasound guided microbiopsies:A case report

Pancreatic cysts are increasingly diagnosed due to expanding use of cross-sectional imaging,but current diagnostic modalities have limited diagnostic accuracy.Recently,a novel through-the-needle microbiopsy forceps has become available,offering the possibility of obtaining cyst-wall biopsies.We present a case of 41-year-old male with chronic pancreatitis and a 2-cm pancreatic cyst,initially considered a pseudocyst.Subsequently,endoscopic ultrasou-nd guided microbiopsies were successfully obtained,which surprisingly revealed an intraductal papillary mucinous neoplasm of mixed subtype with low grade dysplasia.In conclusion,obtaining biopsies from the wall of the pancreatic cystic lesions with this novel instrument is feasible and,as demonstrated in this case,can possibly alter the clinical outcome.Microbiopsies offered enough cellular material,allowing supplemental gene mutation analysis,which combined with other modalities could lead to a more individual approach when treating pancreatic cysts.However,prospective studies are warranted before routine clinical implementation.     

Concomitant pancreatic adenocarcinoma in a patient with branch-duct intraductal papillary mucinous neoplasm

Branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are pre-malignant pancreatic cystic lesions which carry a small risk of malignant transformation within the cyst. Guidelines exist with respect to surveillance of the cysts using computed tomography, magnetic resonance imaging, and/or endoscopic ultrasound (EUS). There are reports that patients with IPMNs are at increased risk of developing pancreatic adenocarcinoma, which arises in an area separate to the IPMNs. We present two cases of pancreatic adenocarcinoma arising within the parenchyma, distinct from the IPMN-associated cyst, identified with EUS. This case report highlights that patients with BD-IPMN are at increased risk for pancreatic adenocarcinoma separate from the cyst and also the importance for endosonographers to carefully survey the rest of the pancreatic parenchyma separate from the cyst in order to identify small pancreatic adenocarcinomas.     

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.     

Endoscopic ultrasonography findings of pancreatic parenchyma for predicting subtypes of intraductal papillary mucinous neoplasms

Background and aimsThe subtypes of intraductal papillary mucinous neoplasms (IPMNs) are closely associated with the clinicopathological behavior and recurrence after surgical resection. However, there are no established non-invasive methods to confirm the subtypes of IPMNs without surgery. The aim of this study is to predict the subtypes of IPMNs using the findings of endoscopic ultrasonography (EUS).MethodsSixty-two consecutive patients with IPMNs who underwent EUS before surgery were retrospectively reviewed. The following EUS findings were analyzed and their relationship with the subtypes was evaluated: diameter of the main pancreatic duct, cyst size, number of cysts, height of mural nodule, early chronic pancreatitis (CP) finding, fatty parenchyma and atrophic parenchyma.ResultsThe subtypes of IPMNs were as follows: gastric (G)-type 38 (61%), intestinal (I) -type 14 (23%) and pancreatobiliary (PB) -type 10 (16%). Fatty parenchyma was significantly associated with G-type (P < 0.0001). Early CP findings ≥2 and atrophic parenchyma were significantly correlated with I-type (P < 0.0001). PB-type was significantly associated with pancreatic parenchyma without early CP findings or fatty degeneration in comparison to the other subtypes (P < 0.0001). Using the above characteristic EUS findings, the sensitivity, specificity, and accuracy were as follows: 63%, 92% and 74%, respectively, in G-type, 57%, 96% and 87% in I-type, and 90%, 94% and 94% in PB-type.ConclusionsThe evaluation of EUS findings, especially focused on the pancreatic parenchyma, has the potential to predict the subtypes of IPMN.     

Appraisal of needle-based confocal laser endomicroscopy in the diagnosis of pancreatic cysts

Nearly 2.5% of cross-sectional imaging studies will report a finding of a cystic pancreatic lesion. Eventhough most of these are incidental findings, it remains very concerning for both patients and treating clinicians. Differentiating and predicting malignant transformation in pancreatic cystic lesions is clinically challenging. Current evaluation of suspicious cystic lesions includes a combination of radiologic imaging, endoscopic ultrasound(EUS) and cyst fluid analyses. Despite these attempts, precise diagnostic stratification among nonmucinous, mucinous, and malignant cystic lesions is often not possible until surgical resection. EUS-guided needle based confocal laser endomicroscopy(n CLE) for evaluation of pancreatic cysts is emerging as a powerful technique with remarkable potential. Though limited imaging data from 3 large clinical trials(INSPECT, DETECT and CONTACT) are currently the reference standard for n CLE imaging, nonetheless these have not been validated in large studies. The aim of this review article is to review the evolving role of EUS-guided n CLE in management of pancreatic cystic lesions in terms of its significance, adverse events, limitations, and implications.     

Lesiones quísticas de páncreas. Diagnóstico diferencial y estrategia de tratamiento

The differential diagnosis of pancreatic cystic lesions includes non-neoplastic lesions and neoplastic epithelial lesions. Given that management is determined by the risk for malignant progression, associated symptoms, and other characteristics, an accurate diagnosis is imperative. The present review attempts to provide a critical path that facilitates the characterization and management of pancreatic cystic lesions.     

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.     

Evaluation of diagnostic cytology via endoscopic naso-pancreatic drainage for pancreatic tumor

AIM: To evaluate the usefulness of cytology of the pancreatic juice obtained via the endoscopic naso-pancreatic drainage tube(ENPD-C).METHODS: ENPD was performed in cases where a diagnosis could not be made other than by using en-doscopic retrograde cholangiopancreatography and in cases of pancreatic neoplasms or cystic tumors, includ-ing intraductal papillary mucinous neoplasm(IPMN) suspected to have malignant potential. 35 patients(21 males and 14 females) underwent ENPD between January 2007 and June 2013. The pancreatic duct was imaged and the procedure continued in one of ENPD-C or ENPD-C plus brush cytology(ENPD-BC). We checked the cytology result and the final diagnosis.RESULTS: The mean patient age was 69 years(range, 48-86 years). ENPD-C was performed in 24 cases andENPD-C plus brush cytology(ENPD-BC) in 11 cases. The ENPD tube was inserted for an average of 3.5 d. The final diagnosis was confirmed on the basis of the resected specimen in 18 cases and of follow-up findings at least 6 mo after ENPD in the 18 inoperable cases. Malignancy was diagnosed in 21 cases and 14 patients were diagnosed as having a benign condition. The ratios of class Ⅴ/Ⅳ:Ⅲ:Ⅱ/Ⅰ?findings were 7:7:7 in malignant cases and 0:3:11 in benign cases. The sensitivity and specificity for all patients were 33.3% and 100%, re-spectively. The cytology-positive rate was 37.5%(6/16) for pancreatic cancer. For IPMN cases, the sensitivity and specificity were 33% and 100%, respectively.CONCLUSION: Sensitivity may be further increased by adding brush cytology. Although we can diagnosis cancer in cases of a positive result, the accuracy of ENPD-C remains unsatisfactory.     

Clinical approach to incidental pancreatic cysts

The approach to incidentally noted pancreatic cysts is constantly evolving. While surgical resection is indicated for malignant or higher risk cysts, correctly identifying these highest risk pancreatic cystic lesions remains difficult. Using parameters including cyst size, presence of solid components, and pancreatic duct involvement, the 2012 International Association of Pancreatology(IAP) and the 2015 American Gastroenterological Association(AGA) guidelines have sought to identify the higher risk patients who would benefit from further evaluation using endoscopic ultrasound(EUS). Not only can EUS help further assess the presence of solid component and nodules, but also fine needle aspiration of cyst fluid aids in diagnosis by obtaining cellular, molecular, and genetic data. The impact of new endoscopic innovations with novel methods of direct visualization including confocal endomicroscopy require further validation. This review also highlights the differences between the 2012 IAP and 2015 AGA guidelines, which include the thresholds for sending patients for EUS and surgery and methods, interval, and duration of surveillance for unresected cysts.     

胰腺导管内管状乳头状肿瘤三例临床病理学特征

目的 分析胰腺导管内管状乳头状肿瘤(ITPN)的临床特征、病理形态学特征以及K-ras 基因突变状况,以提高对该病的认知度.方法 收集上海长海医院3例ITPN,并综合文献报道的16例资料,分析它们的临床表现、肿瘤的大体及病理组织学改变、免疫表型、K-ras基因突变状况,并与81例胰腺导管内黏液性乳头状肿瘤(IPMT)进行对比.结果 3例ITPN患者均为男性,中位年龄43岁,临床症状无特异性.2例肿瘤位于胰头部,1例位于胰体尾部;镜下表现为导管内实性团块,排列呈腺管样及筛孔状,细胞核中至重度异型,1例伴有浸润性导管腺癌成分并见胰周淋巴结转移;肿瘤细胞上皮标志物细胞角蛋白均阳性表达,部分肿瘤细胞p53阳性表达,神经内分泌标志物CHR、NSE及黏蛋白家族中的MUC2、MUC5AC均阴性表达,未检测到K-ras基因突变.IPMT的肿瘤细胞呈乳头状排列,可见筛孔结构;大部分细胞为黏液上皮或含较多杯状细胞(肠型),少部分为嗜酸性上皮(嗜酸细胞型)和立方上皮(胰胆管型);MUC2和MUC5AC表达阳性,K-ras基因突变发生率约50％.结论 ITPN是一种新的胰腺肿瘤类型,具有与IPMT不同的临床病理学特征.     

Intraductal papillary mucinous carcinoma with atypical manifestations： Report of two cases

Intraductal papillary mucinous neoplasms(IPMNs)are a well-characterized group of mucin-producing cystic neoplasms of the clear malignant potential type.We report here two cases of intraductal papillary mucinous carcinoma(IPMC)with atypical manifestations.In one case,we discussed a pseudomyxoma peritonei caused by a ruptured IPMC.In the other case we discussed the fistulization of IPMC into the stomach and duodenum.These two cases suggest that IPMN can either spontaneously rupture causing mucinous materials to spill into the free abdominal cavity or directly invade adjacent organs resulting in fistula development.     

Endoscopic ultrasound in the diagnosis of pancreatic intraductal papillary mucinous neoplasms

Pancreatic cystic lesions are increasingly recognised due to the widespread use of different imaging modalities.Intraductal papillary mucinous neoplasms(IPMNs)of the pancreas represent a common,but also heterogeneous group of cystic tumors with a significant malignant potential.These neoplasms must be differentiated from other cystic tumors and properly classified into their different types,main-duct IPMNs vs branchduct IPMNs.These types have a different malignant potential and therefore,different treatment strategies need to be implemented.Endoscopic ultrasound(EUS)offers the highest resolution of the pancreas and can aid in the differential diagnosis,classification and differentiation between benign and malignant tumors.The addition of EUS fine-needle aspiration can supply further information by obtaining fluid for cytology,measurement of tumor markers and perhaps DNA analysis.Novel techniques,such as the use of contrast and sophisticated equipment,like intraductal probes can provide information regarding malignant features and extent of these neoplasms.Thus,EUS is a valuable tool in the diagnosis and appropriate management of these tumors.     

Intraductal papillary mucinous neoplasm in chronic calcifying pancreatitis： Egg or hen？

Intraductal papillary mucinous neoplasm (IPMN) is an increasingly reported entity. Extensive pancreatic calcification is generally thought to be a sign of chronic pancreatitis, but it may occur simultaneously with IPMN leading to diagnostic difficulties. We report a case of a patient initially diagnosed with chronic calcifying pancreatitis who was later shown to have a malignant IPMN. This case illustrates potential pitfalls in the diagnosis of IPMN in the case of extensive pancreatic calcification as well as clues that may lead the clinician to suspecting the diagnosis. The possible mechanisms of the relation between pancreatic calcification and IPMN are also reviewed.     

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.     

Role of endoscopic ultrasound in the screening and follow-up of high-risk individuals for familial pancreatic cancer

Managing familial pancreatic cancer(FPC)is challenging for gastroenterologists,surgeons and oncologists.High-risk individuals(HRI)for pancreatic cancer(PC)(FPC or with germline mutations)are a heterogeneous group of subjects with a theoretical lifetime cumulative risk of PC over 5%.Screening is mainly based on annual magnetic resonance imaging(MRI)and endoscopic ultrasound(EUS).The goal of screening is to identify early-stage operable cancers or high-risk precancerous lesions(pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasms with high-grade dysplasia).In the literature,target lesions are identified in 2%-5%of HRI who undergo screening.EUS appears to provide better identification of small solid lesions(0%-46%of HRI)and chronicpancreatitis-like parenchymal changes(14%-77%of HRI),while MRI is probably the best modality to identify small cystic lesions(13%-49%of HRI).There are no specific studies in HRI on the use of contrast-enhanced harmonic EUS.EUS can also be used to obtain tissue samples.Nevertheless,there is still limited evidence on the accuracy of imaging procedures used for screening or agreement on which patients to treat.The cost-effectiveness of screening is also unclear.Certain new EUS-related techniques,such as searching for DNA abnormalities or protein markers in pancreatic fluid,appear to be promising.     

Updates in diagnosis and management of pancreatic cysts

Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma, mucinous cystic neoplasm and intraductal papillary mucinous neoplasm. Risk stratifying pancreatic cysts is important in deciding whether patients may benefit from endoscopic ultrasound (EUS) or surgical resection. Surgery should be reserved for patients with malignant cysts or cysts at high risk for developing malignancy as suggested by various risk features including solid mass, nodule and dilated main pancreatic duct. EUS may supplement magnetic resonance imaging findings for cysts that remain indeterminate or have concerning features on imaging. Various cyst fluid markers including carcinoembryonic antigen, glucose, amylase, cytology, and DNA markers help distinguish mucinous from nonmucinous cysts. This review will guide the practicing gastroenterologist in how to evaluate incidental pancreatic cysts and when to consider referral for EUS or surgery. For presumed low risk cysts, surveillance strategies will be discussed. Managing pancreatic cysts requires an individualized approach that is directed by the various guidelines.