Needle-Based Confocal Laser Endomicroscopy for Evaluation of Cystic Neoplasms of the Pancreas.

BACKGROUND: The accurate diagnosis of cystic neoplasms of the pancreas (CNP) with current diagnostic methods is limited. Endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) is a new technique which can obtain images from the cyst wall during EUS-fine needle aspiration (EUS-FNA). The aim of this study was to assess the safety, feasibility, and diagnostic value of nCLE for CNP. METHODS: Patients who underwent EUS-FNA to evaluate a CNP larger than 2 cm were enrolled. The cyst was punctured with 19-G FNA needle preloaded with an nCLE probe. The images from different areas of the cyst wall were recorded. Using the final diagnosis defined by surgery or EUS-FNA cyst fluid analysis, the accuracy of the confocal images was defined. RESULTS: The procedure and image acquisition was successful in 18 of the 20 patients. Predefined typical structures for mucinous cysts were visualized in 8 of 12 (66%) cysts but none of the non-mucinous cysts. The superficial vascular network which is a typical finding of serous cysts was observed in 2 of 3 patients. The sensitivity, specificity, and diagnostic accuracy of the findings of epithelial structures by nCLE were 66, 100, and 80%, respectively, for a mucinous cyst diagnosis. All patients tolerated the procedure well, and no adverse effects were determined. CONCLUSION: nCLE was found to be safe and feasible with high technical success, in this pilot study. With an overall accuracy of 80%, it has the potential to contribute to the diagnosis of CNP with specific imaging.

Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms.

BACKGROUND AND AIM: Molecular analysis of pancreatic cyst fluid (PCF) has been proposed as a novel method for differentiating pancreatic cystic lesions (PCL). The present study aimed to investigate the value of GNAS testing when added to KRAS and carcinoembryonic antigen (CEA) testing of PCF for the diagnosis of intraductal papillary mucinous neoplasms (IPMN). METHODS: Prospectively collected endoscopic ultrasonography fine-needle aspiration (EUS-FNA) data were analyzed retrospectively for GNAS and KRAS mutations and CEA results. IPMN were histologically confirmed or supported by imaging and EUS-FNA findings (KRAS, CEA, cytology). Performance characteristics of GNAS added to KRAS and CEA for the diagnosis of IPMN were calculated. RESULTS: The study population consisted of 197 patients with cyst fluid test results. Cysts were histologically classified in 33 patients and by clinical criteria in 164 patients. The IPMN group included 108 patients and the non-IPMN group included 89 patients. GNAS was positive in 51 patients (47.2%) with IPMN. Forty-two of these patients (82.3%) also had a KRAS mutation. Adding GNAS to KRAS increased the diagnostic accuracy from 76.6% to 79.1% (P > 0.05). Adding GNAS to CEA increased the diagnostic accuracy from 66.4% to 80.7 % (P < 0.05), but did not achieve a diagnostic superiority to KRAS testing alone (80.7% vs 76.6%, P > 0.05). The diagnostic accuracy of the triple combination was significantly better than all single tests (P < 0.05). CONCLUSION: GNAS mutation is a highly specific test for IPMN. When GNAS testing is added to CEA and KRAS, a significantly greater overall accuracy (86.2%) is achieved.

Endoscopic Therapy With Lumen-apposing Metal Stents Is Safe and Effective for Patients With Pancreatic Walled-off Necrosis.

BACKGROUND & AIMS: Endoscopic ultrasound-guided transmural drainage and necrosectomy have become the standard treatment for patients with pancreatic walled-off necrosis (WON). Lumen-apposing metal stents (LAMS) have shown success in the management of pancreatic fluid collections. However, there are few data on their specific roles in management of WON. We investigated the efficacy and safety of LAMS in treatment of WON. METHODS: We performed a retrospective multicenter case series of 124 patients with WON who underwent endoscopic transmural drainage by using LAMS at 17 tertiary care centers from January 2014 through May 2015. Patients underwent endoscopic ultrasound-guided cystogastrostomy or cystoenterostomy with placement of an LAMS into the WON collection. At the discretion of the endoscopist, we performed direct endoscopic necrosectomy, irrigation with hydrogen peroxide, and/or nasocystic drain placement. We performed endoscopic retrograde cholangiopancreatography with pancreatic duct stent placement when indicated. Concomitant therapies included direct endoscopic debridement (n = 78), pancreatic duct stent placement for leak (n = 19), hydrogen peroxide-assisted necrosectomy (n = 38), and nasocystic irrigation (n = 22). We collected data for a median time of 4 months (range, 1-34 months) after the LAMS placement. The primary outcomes were rates of technical success (successful placement of the LAMS), clinical success (resolution of WON, on the basis of image analysis, without need for further intervention via surgery or interventional radiology), and adverse events. RESULTS: The median size of the WON was 9.5 cm (range, 4-30 cm). Eight patients had 2 LAMS placed for multiport access, all with technical success (100%). Clinical success was achieved in 107 patients (86.3%) after 3 months of follow-up. Thirteen patients required a percutaneous drain, and 3 required a surgical intervention to manage their WON. The stents remained patent in 94% of patients (117 of 124) and migrated in 5.6% of patients (7 of 124). The median number of endoscopic interventions was 2 (range, 1-9 interventions). CONCLUSIONS: On the basis of a retrospective analysis of 124 patients, endoscopic therapy of WON by using LAMS is safe and effective. Creation of a large and sustained cystogastrostomy or cystoenterostomy tract is effective in the drainage and treatment of WON.

Combined endoscopic trangastric drainage and video assisted retroperitoneal pancreatic debridement - The best of both worlds for extensive pancreatic necrosis with enteric fistulae.

Enteric fistula is a serious complication of necrotizing pancreatitis. Endoscopic transluminal drainage and necrosectomy can significantly reduce the incidence of enterocutaneous fistula after pancreatic debridement. However, endoscopic necrosectomy may not be well-suited to debridement of necrosis that tracks laterally to the paracolic gutters, which is often more efficiently addressed by video-assisted retroperitoneal debridement (VARD). We report the combined use of endoscopic transgastric drainage and VARD for treatment of a 76 year old man with severe necrotizing acute pancreatitis complicated by infected, walled-off pancreatic necrosis. Computed tomography showed laterally tracking pancreatic necrosis and flouroscopic drain injection after percutaneous drainage demonstrated with fistulas to the stomach, duodenum, and colon. The infection and fistulas resolved completely. This approach combined the major advantage of VARD with the major advantage of endoscopic transluminal drainage. We are not aware of any reports of combining these techniques and believe the combination offers a minimally invasive approach for patients with extensive necrosis and a high likelihood of enteric or pancreatic fistulas.

Radiofrequency ablation for the management of occluded biliary metal stents.

Background and study aim: Obstruction of biliary self-expandable metal stents (SEMSs) is seen frequently. Radiofrequency ablation (RFA) causes tissue necrosis. This study aimed to assess the efficacy of RFA for management of occluded SEMS. Patients and methods: Patients with biliary malignancy and treated for an occluded SEMS were retrospectively reviewed. The study group comprised patients treated with RFA using an Habib endoprobe inside the SEMS. The control group comprised patients treated only with insertion of a plastic stent into an occluded SEMS. The end points were; 90-day stent patency rate, time to stent reocclusion, 30-day mortality, and 3 - and 6-month survival rates. Results: During the 5-year study period 25 patients with an occluded SEMS underwent RFA and 25 patients underwent a plastic stent placement only. Both groups were matched for age and diagnosis. Immediate biliary drainage was restored in all patients. In the RFA group, the stenosis was ablated successfully in 14 patients (56 %); ablation failed in 11 and a plastic stent was then inserted into the SEMS for these. The control group had only placement of a plastic stent across the stenosis. Stent patency rate at 90 days was 56 % and 24 % in the RFA and control groups, respectively (P = 0.04). The mean stent patency time was significantly longer in the RFA group compared to the control group (119.5 vs. 65.3 days, P = 0.03). Conclusion: The application of RFA for occluded SEMS improves stent patency. RFA is an alternative treatment of tissue ingrowth in malignant biliary obstruction.

mAb Das-1 is specific for high-risk and malignant intraductal papillary mucinous neoplasm (IPMN).

OBJECTIVE: Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation. DESIGN: mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot. RESULTS: Immunohistochemistry-Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignant IPMNs were 85% and 95%, respectively. Lesional fluid-Samples from low- and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively. CONCLUSIONS: mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification.

Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome.

BACKGROUND: Endoscopic ampullectomy is increasingly performed in patients with familial adenomatous polyposis (FAP)-associated ampullary adenomas. We sought to define the procedure-associated morbidities and long-term outcomes. METHODS: We performed a retrospective chart review of patients with FAP who underwent endoscopic ampullectomy at two tertiary institutions between 1999 and 2010. The severity of duodenal polyposis was classified according to Spigelman's classification. RESULTS: Of 26 FAP patients who underwent endoscopic ampullectomy, 21 arose in the setting of Spigelman's stage II duodenal polyposis. Adverse events associated with endoscopic ampullectomy included acute pancreatitis (19.2%), abdominal pain (7.6%), and bleeding (3.8%). The mean resected adenoma size was 0.99 ± 0.34 cm. Three adenomas (12.0%) contained foci of high-grade dysplasia. Follow-up data were available for 24 patients. The mean follow-up duration was 84.5 ± 36.2 months. Adenoma recurrence was observed in 14 patients (58.3%; 14/24) at a mean of 38.3 months after initial ampullectomy. Adenomas ≥10 mm recurred more frequently than smaller adenomas (76.9 vs. 36.4%; p = 0.002). Positive margins were not associated with higher recurrence rates. No cancers were observed during long-term follow-up. Three patients underwent a Whipple procedure, but none was performed for a recurrent ampullary adenoma. CONCLUSIONS: Endoscopic ampullectomy in FAP can be performed safely. Because ampullary adenomas frequently recur after endoscopic ampullectomy, close surveillance is essential. Smaller tumors are less likely to recur, suggesting a benefit for early recognition of these lesions.

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Next-generation sequencing in the evaluation of biliary strictures in patients with primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a well-described risk factor for the development of cholangiocarcinoma (CCA). Early detection of CCA in these patients is of great importance because it expands options for therapeutic interventions, including liver transplantation. Current diagnostic tests for the evaluation of biliary strictures are limited to biliary brushing (BB) cytology and fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) has become an important diagnostic tool in oncology and may be a useful tool for diagnosing CCA on BBs. It is not clear how NGS performs when it is added to BB cytology and FISH in patients with PSC. METHODS: This study reports the authors' experience with NGS performed as a prospective cotest with cytology and FISH on BBs obtained from 60 patients with PSC followed at Massachusetts General Hospital. A duct with malignancy was defined as a high-risk (HR) stricture with either high-grade dysplasia or CCA. RESULTS: NGS was better than FISH and cytology in detecting HR strictures, which showed multiple genetic mutations in all cases. NGS provided specific mutational information, and NGS results were reproducible in longitudinal samples. CONCLUSIONS: Adding NGS to BB cytology and FISH in the evaluation of biliary strictures for patients with PSC may provide additional information that could help to inform clinical management.

A randomized trial comparing uncovered and partially covered self-expandable metal stents in the palliation of distal malignant biliary obstruction.

BACKGROUND: The most common complication of uncovered biliary self-expandable metal stents (SEMSs) is tumor ingrowth. The addition of an impenetrable covering may prolong stent patency. OBJECTIVE: To compare stent patency between uncovered and partially covered SEMSs in malignant biliary obstruction. DESIGN: Multicenter randomized trial. SETTING: Four teaching hospitals. PATIENTS: Adults with inoperable distal malignant biliary obstruction. INTERVENTIONS: Uncovered or partially covered SEMS insertion. MAIN OUTCOME MEASURES: Time to recurrent biliary obstruction, patient survival, serious adverse events, and mechanism of recurrent biliary obstruction. RESULTS: From October 2002 to May 2008, 129 patients were randomized. Recurrent biliary obstruction was observed in 11 of 61 uncovered SEMSs (18%) and 20 of 68 partially covered SEMSs (29%). The median times to recurrent biliary obstruction were 711 days and 357 days for the uncovered and partially covered SEMS groups, respectively (P = .530). Median patient survival was 239 days for the uncovered SEMS and 227 days for the partially covered SEMS groups (P = .997). Serious adverse events occurred in 27 (44%) and 42 (62%) patients in the uncovered and partially covered SEMS groups, respectively (P = .046). None of the uncovered and 8 (12%) of the partially covered SEMSs migrated (P = .0061). LIMITATIONS: Intended sample size was not reached. Allocation to treatment groups was unequal. CONCLUSIONS: There was no significant difference in time to recurrent biliary obstruction or patient survival between the partially covered and uncovered SEMS groups. Partially covered SEMSs were associated with more serious adverse events, particularly migration.

Endoscopic ultrasound-guided fiducial marker placement in pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Pancreatic cancer (PC) mortality remains high despite advances in therapy. Combination chemoradiotherapy offers modest survival benefit over monotherapy with either. Fiducial markers serve as needed landmarks for image-guided radiotherapy (IGRT). Traditionally, these markers were placed surgically or percutaneously with limitations of each. Endoscopic ultrasound-guided placement overcomes these limitations. AIM: To evaluate the safety, efficacy, and feasibility of endoscopic ultrasound (EUS)-guided fiducial placement for PC undergoing IGRT. METHODS: Articles were searched in MEDLINE, PubMed, and Ovid journals. Pooling was conducted by fixed and random effects models. Heterogeneity was assessed using Cochran's Q test based upon inverse variance weights. RESULTS: Initial search identified 1024 reference articles for EUS-guided fiducial placement in PC. Of these, 261 relevant articles were reviewed. Data was extracted from 11 studies (n = 820) meeting inclusion criteria. Pooled proportion of successful placement was 96.27% (95%CI: 95.35-97.81) with fiducial migration rates low at 4.33% (95%CI: 2.45-6.71). Adverse event rates remained low, with overall pooled proportion of 4.85% (95%CI: 3.04-7.03). CONCLUSION: EUS-guided placement of fiducial markers for IGRT of PC is safe, feasible, and efficacious. The ability to target deep structures under direct visualization while remaining minimally invasive are added benefits. Moreover, the ability to perform fine needle aspiration or celiac plexus neurolysis add value and increase patient-care efficiency. Whether EUS-guided fiducial placement improves outcomes in IGRT or offers any mortality benefits over traditional placement remains unknown and future studies are needed.

Improved Mortality in Necrotizing Pancreatitis with a Multidisciplinary Minimally Invasive Step-Up Approach: Comparison with a Modern Open Necrosectomy Cohort.

BACKGROUND: A minimally invasive step-up (MIS) approach has been associated with reduced morbidity compared with open surgical necrosectomy (OSN) for treatment of necrotizing pancreatitis. We sought to determine whether transitioning from an OSN to an MIS-based approach would result in reduced mortality. MIS interventions included percutaneous drainage, endoscopic transgastric necrosectomy, video-assisted retroperitoneal debridement, sinus tract endoscopic necrosectomy, or a combination of techniques, with selective use of OSN. STUDY DESIGN: We conducted an observational cohort study with retrospective comparison at a single tertiary referral center (2006 through 2019). Eighty-eight patients were treated with OSN and 91 were treated with an MIS-based approach. Baseline characteristics and clinical outcomes were compared between groups. The primary end point was 90-day mortality. RESULTS: There was no difference in baseline characteristics. Ninety-day mortality was 2% with MIS compared with 10% with OSN (p = 0.03). One-year mortality was 3% with MIS compared with 15% with OSN (p = 0.012). The rate of organ failure was lower with MIS (30% vs 45%; p = 0.029), but there was a higher bleeding rate (19% vs 9%; p = 0.064). In the MIS group, 9% were treated with percutaneous drainage, 32% with endoscopic transgastric necrosectomy, 8% with video-assisted retroperitoneal debridement, 15% with sinus tract endoscopic necrosectomy, and 27% with a combination of techniques. CONCLUSIONS: Adoption of a multidisciplinary MIS-based approach to necrotizing pancreatitis resulted in a 5-fold decrease in mortality compared with OSN.

Novel endoscopic therapeutic modalities for superficial neoplasms arising in Barrett's esophagus: a primer for surgical pathologists.

This review introduces some of the novel endoscopic modalities used for the treatment of superficial neoplasms arising in the setting of Barrett's esophagus, namely endoscopic mucosal resection and photodynamic therapy. We describe the appropriate technical details for pathologists to know to effectively communicate with the gastroenterologists as well as the pitfalls in the evaluation of endoscopic mucosal resection specimens and post photodynamic therapy follow-up biopsies.

Biliary infections: spectrum of imaging findings and management.

Infectious cholangitides encompass a wide spectrum of infectious processes affecting the biliary tree. They can have protean clinical and imaging appearances. Some manifest as an acute medical emergency with high mortality if not properly and emergently managed. Others are chronic processes that may predispose a patient to liver failure or cholangiocarcinoma. The clinical and imaging features and the subsequent therapy are dictated by the pathogens involved, the immune status of the host, and the degree and distribution of biliary obstruction. Bacteria cause most cases of infectious cholangitis in Western countries. In other parts of the world, parasites play an important role, either as causative agents or in predisposing the host to bacterial superinfection. Viral cholangitides primarily affect immunocompromised patients. The clinical and imaging features of cholangitis differ between immunocompetent and immunocompromised patients. Imaging plays a pivotal role in diagnosis of infectious cholangitis, helps identify predisposing causes, and demonstrates complications. Moreover, interventional radiology provides tools to treat acute life-threatening biliary infections, chronic entities, and complications.

Peroral cholangioscopy with cholangioscopy-directed biopsies in the diagnosis of biliary malignancies: a systemic review and meta-analysis.

BACKGROUND AND AIM: Accurate diagnosis is essential in the appropriate management of biliary strictures. Our aim is to evaluate the efficacy of cholangioscopy-directed biopsies in differentiating biliary intraductal malignancies from benign lesions. MATERIALS AND METHODS: Articles were searched in Medline, PubMed, and Ovid journals. Pooling was performed by both fixed-effects and random-effects models. Only studies from which a 2×2 table could be constructed for true-positive, false-negative, false-positive, and true-negative values were included. RESULTS: Initial search identified 2110 reference articles for peroral cholangioscopy; of these, 160 relevant articles were selected and reviewed. Data were extracted from 15 studies (N=539) that fulfilled the inclusion criteria. Pooled sensitivity of cholangioscopy-directed biopsies in diagnosing malignancy was 71.9% [95% confidence interval (CI): 66.1-77.1] and pooled specificity was 99.1% (95% CI: 96.9-99.9). The positive likelihood ratio of cholangioscopy-directed biopsies was 18.1 (95% CI: 9.1-35.8), whereas the negative likelihood ratio was 0.3 (95% CI: 0.2-0.4). The pooled diagnostic odds ratio was 71.6 (95% CI: 32.8-156.4). All the pooled estimates calculated by fixed-effects and random-effect models were similar. Summary receiver operating characteristic curves showed an area under the curve of 0.98. The χ heterogeneity for all the pooled accuracy estimates was 5.62 (P=0.96). CONCLUSION: Peroral cholangioscopy with cholangioscopy-directed biopsies has a high specificity in differentiating intraductal malignancies from benign lesions. Cholangioscopy-directed biopsies should be strongly considered for biliary stricture evaluation.