Diagnosis and clinical implications of pancreatobiliary reflux

The sphincter of Oddi is located at the distal end of the pancreatic and bile ducts and regulates the outflow of bile and pancreatic juice. A common channel can be so long that the junction of the pancreatic and bile ducts is located outside of the duodenal wall, as occurs in pancreaticobiliary maljunction （PBM）; in such cases, sphincter action does not functionally affect the junction. As the hydropressure within the pancreatic duct is usually greater than in the bile duct, pancreatic juice frequently refluxes into the biliary duct （pancreatobiliary reflux） in PBM, resulting in carcinogenetic conditions in the biliary tract. Pancreatobiliary reflux can be diagnosed from elevated amylase level in the bile, secretinstimulated dynamic magnetic resonance cholangiop ancreatography, and pancreatography via the minor duodenal papilla. Recently, it has become obvious that pancreatobiliary reflux can occur in individuals without PBM. Pancreatobiliary reflux might be related to biliary carcinogenesis even in some individuals without PBM. Since few systemic studies exist with respect to clinical relevance and implications of the pancreatobiliary reflux in individuals with normal pancreaticobiliary junction, further prospective clinical studies including appropriate management should be performed.

Contrast-enhanced harmonic endoscopic ultrasonography for assessment of lymph node metastases in pancreatobiliary carcinoma

AIM: To assess the usefulness of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for lymph node metastasis in pancreatobiliary carcinoma.METHODS: All patients suspected of pancreatobiliary carcinoma with visible lymph nodes after standard EUS between June, 2009 and January, 2012 were enrolled. In the primary analysis, patients with successful EUS-fine needle aspiration (FNA) were included. The lymph nodes were assessed by several standard EUS variables (short and long axis lengths, shape, edge characteristic and echogenicity), color Doppler EUS variable [central intranodal blood vessel (CIV) presence] and CH-EUS variable (heterogeneous/homogeneous enhancement patterns). The diagnostic accuracy relative to EUS-FNA was calculated. In the second analysis, N-stage diagnostic accuracy of CH-EUS was compared with EUS-FNA in patients who underwent surgical resection.RESULTS: One hundred and nine patients (143 lymph nodes) fulfilled the criteria. The short axis cut-off ≥ 13 mm predicted malignancy with a sensitivity and specificity of 72% and 85%, respectively. These values were 72% and 63% for the long axis cut-off ≥ 20 mm, 62% and 75% for the round shape variable, 81% and 30% for the sharp edge variable, 66% and 61% for the hypoechogenicity variable, 70% and 72% for the CIV-absent variable, and 83% and 91% for the heterogeneous CH-EUS-enhancement variable, respectively. CH-EUS was more accurate than standard and color Doppler EUS, except the short axis cut-off. Notably, three patients excluded because of EUS-FNA failure were correctly N-staged by CH-EUS.CONCLUSION: CH-EUS complements standard and color Doppler EUS and EUS-FNA for assessment of lymph node metastases.

A case of gallbladder carcinoma associated with pancreatobiliary reflux in the absence of a pancreaticobiliary maljunction:A hint for early diagnosis of gallbladder carcinoma

A 62-year-old man with progressive thickening of the gallbladder wall visited our outpatient clinic. The biliary amylase level in the common bile duct was 19900 IU/L and that of the gallbladder was 127000 IU/L, although endoscopic retrograde cholangiopancreatography revealed no pancreaticobiliary maljunction. Histology demonstrated a moderately differentiated adenocarcinoma of the gallbladder. Pancreatobiliary reflux and associated gallbladder carcinoma were confirmed in the present case, in the absence of a pancreaticobiliary maljunction. Earlier detection of the pancreatobiliary reflux and progressive thickening of the gallbladder wall might have led to an earlier resection of the gallbladder and improved this patient＇s poor prognosis.

Use of color Doppler ultrasonography in the diagnosis of anomalous connection in pancreatobiliary disease

AIM: To estimate the detectability of anomalous connection in pancreatobiliary disease (ACPBD) cases, measuring gallbladder wall blood flow (GWBF).METHODS: In the retrospective study, we enrolled 42subjects with gallbladder wall thickening. GWBF velocity was determined as an average value of the peak velocity of color signals on the gallbladder wall, three times in each case. Based on the findings on endoscopic ultrasonography (EUS) or endoscopic retrograde cholangiopancreatography (ERCP), the 42 subjects were divided into 11 cases with ACPBD and 31 cases without ACPBD. In the prospective study, the subjects were 92 cases with gallbladder wall thickening. Using the cut-off level of the flow velocity obtained in the retrospective study, the usefulness of measuring GWBF velocity in diagnosing ACPBD was evaluated.RESULTS: In the retrospective study, imaging of GWBF was obtained in 40 of the 42 subjects. The mean GWBF velocity of the ACPBD cases was 29.4±3.9 cm/s(mean±SD), which was significantly different (P＜0.0001;95% CI 5.48-13.2) from that of the without ACPBD cases(20.1±5.9 cm/s). Based on this result, we prepared a receiver operating characteristic curve, and the cut-off level appropriate for diagnosing ACPBD was estimated to be 25 cm/s. In the prospective study, GWBF was detected in 86 of the 92 subjects. Based on the EUS or ERCP findings, the 92 subjects were divided into 15 cases with ACPBD and 77 cases without ACPBD. When a cut-off level of 25 cm/s was employed, ACPBD could be diagnosed with a sensitivity of 87.0% (13/15) and a specificity of87.3% (62/71).CONCLUSION: Measurement of GWBF velocity, which is less invasive and provides objective values, is very useful for diagnosing ACPBD prior to the development of malignant tumors in cases with gallbladder wall thickening.

Gallbladder carcinoma associated with pancreatobiliary reflux

AIM: To detect the patients with and without pan-creaticobiliary maljunction who had pancreatobiliary reflux with extremely high biliary amylase levels.METHODS: Ninety-six patients, who had diffuse thickness (> 3 mm) of the gallbladder wall and were suspected of having a pancreaticobiliary maljunction on ultrasonography, were prospectively subjected to endoscopic retrograde cholangiopancreatography, and bile in the common bile duct was sampled. Among them, patients, who had extremely high biliary amylase levels (>10 000 IU/L), underwent cholecystectomy, and the clinicopathological findings of those patients with and without pancreaticobiliary maljunction were examined.RESULTS: Seventeen patients had biliary amylase levels in the common bile duct above 10 000 IU/L, including 11 with pancreaticobiliary maljunction and 6 without pancreaticobiliary maljunction. The occurrence of gallbladder carcinoma was 45.5% (5/11) in patients with pancreaticobiliary maljunction, and 50% (3/6) in those without pancreaticobiliary maljunction.CONCLUSION: Pancreatobiliary reflux with extremely high biliary amylase levels and associated gallbladder carcinoma could be identified in patients with and without pancreaticobiliary maljunction, and those patients might be detected by ultrasonography and bile sampling.

Co-occurrence of IPMN and malignant IPNB complicated by a pancreatobiliary fistula: A case report and review of the literature

BACKGROUND Intraductal papillary neoplasm of the bile duct(IPNB) is pathologically similar to intraductal papillary mucinous neoplasm(IPMN). However, there are several significant differences between them. The rate of IPMN associated with extrapancreatic malignancies has been reported to range from 10%-40%, and it may occasionally be complicated with the presence of fistulas. IPMN associated with malignant IPNB is extremely rare and only nine cases have been reported in the literature.CASE SUMMARY We report a 52-year-old man who presented with recurrent cholangitis for nine months. Computed tomography and magnetic resonance cholangiopancreatography showed the common bile duct stricture with dilated pancreatobiliary duct without other abnormal findings. The underlying pathogenesis could not be identified based on the radiologic images. Endoscopic retrograde cholangiopancreatography revealed a pancreatobiliary fistula with dilated main pancreatic duct, biliary stricture with dilated biliary tree, and mucus discharge from the enlarged orifice of the major papilla. The patient underwent SpyGlass cholangiopancreatoscopy due to a suspected mucin-producing biliary neoplasm and indeterminate main pancreatic duct dilatation. Multiple papillary growing neoplasms with vascular images, with the extent of lesions spreading in the biliopancreatic ductal lumens, were identified by SpyGlass. In addition, the presence of a pancreatobiliary fistula was also identified. The patient was diagnosed as having benign IPMN and malignant IPNB with focal invasion by postoperative pathology. Furthermore, varying histological subtypes were present in both IPMN and IPNB. Pylorus-preserving pancreaticoduodenectomy was performed on the patient with excellent results during the 52 month followup period.CONCLUSION We deemed that pancreatography and SpyGlass allowed for an efficient diagnosis of IPMN with pancreatobiliary fistula, whereas the etiology could not be identified by radiologic imaging.

Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids

AIM:To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers.METHODS:DNA was extracted from undiluted pancreatic and biliary fluids.As a surrogate for a genomewide hypomethylation assay,levels of long interspersed nuclear element-1(LINE-1) methylation were analyzed using bisulfite pyrosequencing.CpG island hypermethylation of 10 tumor-associated genes,aryl-hydrocarbon receptor repressor,adenomatous polyposis coli,calcium channel,voltage dependent,T type α1G subunit,insulin-like growth factor 2,O-6-methyl-guanine-DNA methyltransferase,neurogenin 1,CDKN2A,runt-related transcription factor 3(RUNX3),secreted frizzled-related protein 1,and ubiquitin carboxyl-terminal esterase L1(UCHL1),was analyzed using MethyLight.To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1,human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 μmol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h.After the treatment,UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction.RESULTS:Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease(58.7% ± 4.3% vs 61.7% ± 2.2%,P = 0.027;53.8% ± 6.6% vs 57.5% ± 1.7%,P = 0.007);however,LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids(45.4% ± 5.5% vs 58.7% ± 4.3%,P < 0.001).CpG island hypermethylation of tumor-associated genes was detected at various frequencies,but it was not correlated with LINE-1 hypomethylation.Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic(67%) or biliary(70%) fluids from patients with pancreatobiliary cancer.As a single marker,hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers,respectively(100% specificity).Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic(87% sensitivity and 100% specificity) and pancreatobiliary(97% sensitivity and 100% specificity) cancers.Treatment with a demethylating agent,5-AZA-2'-deoxycytidine,restored UCHL1 expression in pancreatobiliary cancer cell lines.CONCLUSION:Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers.

Portal Vein Stenosis Caused by Postoperative Complications after Pancreatobiliary Surgery

Background: Portal vein (PV) stenosis or obstruction is sometimes observed in patients who were performed pancreatobiliary surgery. These conditions such as pancreatic fistulas (PF) and intra-abdominal infections after pancreatobiliary surgery still represent significant clinical issues. In addition, insufficient attention is paid to the fact that severe stenosis of the PV can result in life-threatening complications. Material and Methods: At our institution, lymph node dissection within the hepatoduodenal ligament was performed for biliary or pancreatic neoplasms in 68 patients between October 2005 and April 2017. The diameter of the PV was measured on computed tomography scans obtained before and after the operation. PV stenosis was defined as a >50% reduction in the diameter of the PV. The degree of PF (Pancreatic Fistula) was defined by the International Study Group of Pancreatic Fistula after pancreaticoduodenectomy. Furthermore, the Clavien-Dindo (CD) classification was used to assess the complications that occurred in cases in which pancreatojejunostomy was not performed. The relationship between the degree of PV stenosis and the occurrence of postoperative complications was analyzed. Results: The overall frequency of PF was 56.3% (18 patients). Grade B or C PF occurred in 5 patients (15.6%). In the present small series, a correlation was detected between the degree of PV stenosis and the occurrence of postoperative complications after pancreatobiliary surgery (p Conclusions: Clinicians should keep in mind that the PV can narrow in cases in which grade B or C PF or intra-abdominal abscesses occur after pancreatobiliary surgery.

Comparative Study between Endoscopic Ultrasonography and Transabdominal Ultrasonography in the Assessment of Pancreatobiliary Diseases (with Literatures Review)

Background: Endoscopic ultrasonography (EUS) and transadominal ultrasonography (TUS) are two imaging investigations which can be used to assess pancreatobiliary status, although both of these imaging techniques are operator and machine dependent, but they have different sensitivity and specificity in detecting pancreatobiliary diseases. Objective: To compare the diagnostic value of EUS versus TUS in the assessment of pancreatobiliary diseases. Patients and Methods: This study was conducted in KCGH (Kurdistan Center for Gastroenterology and Hepatology) in Sulaimani city. Iraqi Kurdistan;the duration of study was 14 months and conducted after approval of Iraqi board ethical committee. One hundred cases were enrolled in the study: 52 of them were females and 48 were males;their ages ranged between 16 - 90 years;informed consent was taken from all patients;all patients underwent proper clinical evaluation;TUS, EUS and Oesophagogastroduodenoscopy (OGD), and in some of them (25 patients) Endoscopic Retrograde Cholangiopancreatography (ERCP), CT scan of abdomen and laboratory investigations were done. Results: EUS detected more cases with common bile duct (CBD) dilatation, CBD stones and pancreatic space occupying lesion (SOL) than TUS, but the differences in the results were not statistically significant. Also EUS detected more cases of intra-abdominal lymph nodes (LNs) and ampullary/peri-ampullary neoplasms than TUS and the differences in the results were statistically significant. Conclusions: Eus is more sensitive than TUS in diagnosing CBD dilatation;it has higher sensitivity than TUS in suspected pancreatobiliary neoplasms;furthermore, EUS can be used for staging and resectability assessment of pancreatobiliary neoplasia.

Current status of the biliary tract malformation

The choledochal cyst(CC)can be better termed as biliary tract malformation because of the close association of embryology and etiology in the causation of CC.Contrary to Babbitt's postulation of reflux,damage and dilatation,reflux was not demonstrable as the causative factor in all varieties of CC.High pressure in the biliary system,otherwise termed ductal hypertension,is put forth as an alternative to explain the evolution of CC.The forme fruste type,which does not find a place in the standard classification,typifies the ductal hypertension hypothesis.Hence a closer,in-depth review would be able to highlight this apt terminology of biliary tract malformation.

Endoscopic diagnosis of pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a junction of the pancreatic and bile ducts located outside the duodenal wall, usually forming a markedly long common channel. As the action of the sphincter of Oddi does not functionally affect the junction in PBM patients, continuous pancreatobiliary reflux occurs, resulting in a high incidence of biliary cancer. PBM can be divided into PBM with biliary dilatation (congenital choledochal cyst) and PBM without biliary dilatation (maximal diameter of the bile duct ≤ 10 mm). The treatment of choice for PBM is prophylactic surgery before malignant changes can take place. Endoscopic retrograde cholangiopancreatography (ERC P) is the most effective examination method for close obs ervation of the pattern of the junction site. When the communication between the pancreatic and bile ducts is maintained, despite contraction of the sphi ncter on ERCP, PBM is diagnosed. In these pat ients, levels of pancreatic enzymes in the bile are gene rally elevated, due to continuous pancreatobiliary reflux via a long common channel. Magnetic resonance cholangiopancreatography and 3D-computed tomography can diagnose PBM, based on findings of an anomalous union between the common bile duct and the pancreatic duct, in addition to a long common channel. Endoscopic ultrasonography and intraductal ultra sonography can demonstrate the junction outside the duodenal wall, and are useful for the diagnosis of asso ciated biliary cancer. Gallbladder wall thickness on ultra so nography can be a screening test for PBM.

Ampulla of Vater carcinoma: Molecular landscape and clinical implications

Ampulla of Vater is a peculiar anatomical structure, characterized by the crossroad of three distinct epithelia: Intestinal, ductal pancreatic and biliary. Adenocarcinomas arising in this area represent an opportunity to understand the comparative biology of all periampullary malignancies. These neoplasms can exhibit intestinal, pancreaticobiliary or mixed features, whereas the subclassification based on morphology and immunohistochemical features failed in demonstrating a robust prognostic reliability. In the last few years, the molecular landscape of this tumor entity has been uncovered, identifying alterations that may serve as prognostic and predictive biomarkers. In this review, the histological and genetic characteristics of ampullary carcinomas are discussed, taking into account the main clinical and therapeutic implications related to this tumor type as well.

Ampullary cancer of intestinal origin and duodenal cancer-A logical clinical and therapeutic subgroup in periampullary cancer

Periampullary cancers include pancreatic, ampullary, biliary and duodenal cancers. At presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. This can result in difficulty in defining the primary site of origin in all but the smallest tumors due to anatomical proximity and architectural distortion. This has led to variation in the reported proportions of resected periampullary cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary(16%-50%), bile duct(5%-39%), and duodenal cancer(3%-17%). Patients with resected duodenal and ampullary cancers have a better reported median survival(29-47 mo and 22-54 mo) compared to pancreatic cancer(13-19 mo). The poorer survival with pancreatic cancer relates to differences in tumour characteristics such as a higher incidence of nodal, neural and vascular invasion. While small ampullary cancers can present early with biliary obstruction, pancreatic cancers need to reach a certain size before biliary obstruction ensues. This larger size at presentation contributes to a higher incidence of resection margin involvement in pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. This avoids relying on histomorphology alone, as even some poorly differentiated cancers preserve the histomolecular profile of their mucosa of origin. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin. Unlike pancreatic cancers, KRAS mutation occurs in only approximately a third of ampullary and duodenal cancers. Future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. The addition of anti-epidermal growth factor receptor therapy in this group warrants study.

Improved techniques for double-balloon-enteroscopy-assisted endoscopic retrograde cholangiopancreatography

AIM: To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy. METHODS: Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth Ⅱ gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing,selectively applying contrast medium, and CO2 insufflations. RESULTS: The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96% success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96%), Billroth Ⅱ reconstruction (94%), or pancreatoduodenectomy (100%), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89%). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88 %), Billroth Ⅱ reconstruction (89%), or pancreatoduodenectomy (100%), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100%) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth Ⅱ reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5%); perforation of the long limb in a patient with Billroth Ⅱ anastomosis.CONCLUSION: Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.

Endoscopic ultrasound-guided fine-needle aspiration biopsy-Recent topics and technical tips

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is a useful procedure that enables reliable pathological diagnoses of pancreatobiliary diseases, subepithelial lesions, and swollen lymph nodes. In recent years, a pathological diagnosis based on EUS-FNA has made it possible to provide accurate treatment methods not only in these fields, but also in respiratory organs and otorhinolaryngology. This review discusses the latest topics pertaining to EUS-FNA as well as procedural tips.

Colonic and anal metastases from pancreato-biliary malignancies

Pancreato-biliary malignancies often present with locally advanced or metastatic disease.Surgery is the mainstay of treatment although less than 20%of tumours are suitable for resection at presentation.Common sites for metastases are liver,lungs,lymph nodes and peritoneal cavity.Metastatic disease carries poor prognosis,with median survival of less than 3 mo.We report two cases where metastases from pancreato-biliary cancers were identified in the colon and anal canal.In both cases specific immunohistochemical staining was utilised in the diagnosis.In the first case,the pre-senting complaint was obstructive jaundice due to an ampullary tumour for which a pancreato-duodenectomy was carried out.However,the patient re-presented 4wk later with an atypical anal fissure which was found to be metastatic deposit from the primary ampullary adenocarcinoma.In the second case,the patient presented with obstructive jaundice due to a biliary stricture.Subsequent imaging revealed sigmoid thickening,which was confirmed to be a metastatic deposit.Distal colonic and anorectal metastases from pancreatobiliary cancers are rare and can masquerade as primary colorectal tumours.The key to the diagnosis is the specific immunohistochemical profile of the intestinal lesion biopsies.