Extrapancreatic Location Research Articles

Prognostic Significance of Intratumoral and Peritumoral Budding in Distal Extrahepatic Bile Duct Carcinoma

Introduction: Although tumor budding (TB) has been recognized as a representative adverse prognosticator in gastrointestinal malignancies, it is not well elucidated in distal extrahepatic bile duct carcinoma (DBDC). Herein, we investigated the prognostic significance of peritumoral (PTB) and intratumoral (ITB) budding according to the modified DBDC staging of the 8th edition of the American Joint Committee on Cancer. Methods: PTB and ITB were independently evaluated in a cohort of DBDC patients (n = 410) based on the 2016 International Tumor Budding Consensus Conference. Results: High levels of PTB (PTBHigh, ≥ grade-2) and ITB (ITBHigh, ≥ grade-3) were identified in 316 (77%) and 238 (58%) cases, respectively. In univariate analysis, PTBHigh and ITBHigh, larger size and sclerosing tumor growth pattern, higher histologic grade, extrapancreatic location, adenocarcinomas unrelated to intraductal papillary neoplasm of the bile duct, pancreatic, duodenal, and lymphovascular invasion, perineural invasion, cancer involvement of the bile duct resection margin, nodal metastasis, and higher T and N categories and disease stages were associated with shorter patient overall survival (OS) times. In multivariate analysis, PTBHigh and ITBHigh remained poor independent prognostic indicators of OS in DBDC patients. Specifically, ITBHigh could predict poor prognosis in patients with stage I (T1N0) DBDC. Conclusions: Both PTBHigh and ITBHigh were strong prognostic indicators in patients with DBDC. Thus, ITB could be used to predict worse prognoses in patients with DBDC, in which PTB is difficult to assess, especially for patients with stage I (T1N0) DBDC.

Risk prediction platform for pancreatic fistula after pancreatoduodenectomy using artificial intelligence.

BACKGROUNDDespite advancements in operative technique and improvements in postoperative managements, postoperative pancreatic fistula (POPF) is a life-threatening complication following pancreatoduodenectomy (PD). There are some reports to predict POPF preoperatively or intraoperatively, but the accuracy of those is questionable. Artificial intelligence (AI) technology is being actively used in the medical field, but few studies have reported applying it to outcomes after PD.AIMTo develop a risk prediction platform for POPF using an AI model.METHODSMedical records were reviewed from 1769 patients at Samsung Medical Center who underwent PD from 2007 to 2016. A total of 38 variables were inserted into AI-driven algorithms. The algorithms tested to make the risk prediction platform were random forest (RF) and a neural network (NN) with or without recursive feature elimination (RFE). The median imputation method was used for missing values. The area under the curve (AUC) was calculated to examine the discriminative power of algorithm for POPF prediction.RESULTSThe number of POPFs was 221 (12.5%) according to the International Study Group of Pancreatic Fistula definition 2016. After median imputation, AUCs using 38 variables were 0.68 ± 0.02 with RF and 0.71 ± 0.02 with NN. The maximal AUC using NN with RFE was 0.74. Sixteen risk factors for POPF were identified by AI algorithm: Pancreatic duct diameter, body mass index, preoperative serum albumin, lipase level, amount of intraoperative fluid infusion, age, platelet count, extrapancreatic location of tumor, combined venous resection, co-existing pancreatitis, neoadjuvant radiotherapy, American Society of Anesthesiologists’ score, sex, soft texture of the pancreas, underlying heart disease, and preoperative endoscopic biliary decompression. We developed a web-based POPF prediction platform, and this application is freely available at http://popfrisk.smchbp.org.CONCLUSIONThis study is the first to predict POPF with multiple risk factors using AI. This platform is reliable (AUC 0.74), so it could be used to select patients who need especially intense therapy and to preoperatively establish an effective treatment strategy.

Pancreatic-Type Mixed Acinar Neuroendocrine Carcinoma Arising in the Common Bile Duct: A Case Report

Abstract Mixed acinar neuroendocrine carcinoma (MAcNEC) of pancreatic type arising in an extrapancreatic location is extremely rare. We present a case of a 70-year-old woman with constipation, abdominal discomfort, and jaundice. Imaging studies revealed a 1.8-cm solid mass in the common bile duct causing dilatation of intrahepatic and extrahepatic bile ducts, which was resected. Microscopically, the tumor was limited to the wall of the bile duct, without involvement of the pancreas, and was composed of solid sheets and nests of relatively monomorphic cells with minimal to moderate amounts of cytoplasm, granular chromatin, focally prominent nucleoli, and up to 160 mitoses per 10 high-power fields. Immunohistochemistry showed equal to or greater than 30% positivity for synaptophysin, chromogranin, chymotrypsin, and trypsin. A diagnosis of MAcNEC was rendered. Immunohistochemistry plays a pivotal role in the identification of these tumors and discrimination from other related entities, neuroendocrine neoplasms in particular. Because pancreatic heterotopia has been described in the common bile duct, we postulate that this case of MAcNEC in the common bile duct, the first to be reported in the literature, may have arisen via malignant transformation of pancreatic heterotopia.

A rare case of chronic calcificpancreatitis with intrahepatic andsplenic pseudocysts

Pancreatic pseudocyst is a well-defined collection of fluid rich in pancreatic enzymes which occurs as a complication of pancreatitis. They are mostly located in the head and body of the pancreas while few are found in extra-pancreatic locations like mediastinum, liver, pelvis, pleura and spleen. However intrahepatic pseudocyst is a rare complication of pancreatitis with only 34 such cases being reported in English literature till the year 2009. Around 1 in 100 cases of pancreatic pseudocyst show extension into spleen.

Intrahepatic pancreatic pseudocyst: A review of the world literature.

AIMTo investigate and summarize the literature regarding the diagnosis and management of intrahepatic pancreatic pseudocysts (IHPP).METHODSA literature search was performed using PubMed (MEDLINE) and Google Scholar databases, followed by a manual review of reference lists to ensure that no articles were missed. All articles, case reports, systematic reviews, letters to editors, and abstracts were analyzed and tabulated. Bivariate analyses were performed, with significance accepted at P < 0.05. Articles included were primarily in the English language, and articles in other languages were reviewed with native speakers or, if none available, were translated with electronic software when possible.RESULTSWe found 41 published articles describing 54 cases since the 1970s, with a fairly steady rate of publication. Patients were predominantly male, with a mean age of 49 years. In 42% of published cases, the IHPP was the only reported pseudocyst, but 58% also had concurrent pseudocysts in other extrapancreatic locations. Average IHPP size was 9.5 cm and they occurred most commonly (48%) in the left hemiliver. Nearly every reported case was managed with an intervention, most with a single intervention, but some required up to three interventions. Percutaneous treatment with either simple aspiration or with an indwelling drain were the most common interventions, frequently performed along with stenting of the pancreatic duct. The size of the IHPP correlated significantly with both the duration of treatment (P = 0.006) and with the number of interventions required (P = 0.031). The duration of therapy also correlated with the initial white blood cell (WBC) count (P = 0.048).CONCLUSIONDiagnosis of IHPP is difficult and often missed. Initial size and WBC are predictive of the treatment required. With appropriate intervention, most patients achieve resolution.

Mutational spectrum of intraepithelial neoplasia in pancreatic heterotopia

Heterotopic pancreatic parenchyma recapitulates the normal pancreas in extrapancreatic locations and, on rare occasions, can even give rise to pancreatic adenocarcinoma. The genetic signatures of pancreatic adenocarcinoma and its precursor lesions are well characterized. We explored the genetic alterations in precursor lesions (intraductal papillary mucinous neoplasms [IPMN], pancreatic intraepithelial neoplasia [PanIN]) in patients with pancreatic heterotopias but without concomitant pancreatic ductal adenocarcinomas. This allowed us to determine whether the stereotypical dysplasia--infiltrating carcinoma sequence also occurs in these extrapancreatic foci. Seven cases of heterotopic pancreas with ductal precursor lesions were identified. These included 2 IPMNs with focal high-grade dysplasia and 5 PanINs with low- to moderate-grade dysplasia (PanIN grades 1-2). Neoplastic epithelium was microdissected and genomic DNA was extracted. Sequencing of commonly mutated hotspots (KRAS, TP53, CDKN2A, SMAD4, BRAF, and GNAS) in pancreatic ductal adenocarcinoma and its precursor lesions was performed. Both IPMNs were found to have KRAS codon 12 mutations. The identification of KRAS mutations suggests a genetic pathway shared with IPMN of the pancreas. No mutations were identified in our heterotopic PanINs. One of the possible mechanisms for the development of dysplasia in these lesions is field effect. At the time of these resections, there was no clinical or pathologic evidence of a prior or concomitant pancreatic lesion. However, a clinically undetectable lesion is theoretically possible. Therefore, although a field effect cannot be excluded, there was no evidence for it in this study.

Hydatid cyst of the pancreas: Report of an undiagnosed case of pancreatic hydatid cyst and brief literature review.

To overview the literature on pancreatic hydatid cyst (PHC) disease, a disease frequently misdiagnosed during preoperative radiologic investigation. PubMed, Medline, Google Scholar, and Google databases were searched to identify articles related to PHC using the following keywords: hydatid cyst, hydatid disease, unusual location of hydatid cyst, hydatid cyst and pancreas, pancreatic hydatid cyst, and pancreatic echinococcosis. The search included letters to the editor, case reports, review articles, original articles, meeting presentations and abstracts that had been published between January 2010 and April 2014 without any restrictions on language, journal, or country. All articles identified and retrieved which contained adequate information on the study population (including patient age and sex) and disease and treatment related data (such as cyst size, cyst location, and clinical management) were included in the study; articles with insufficient demographic and clinical data were excluded. In addition, we evaluated a case of a 48-year-old female patient with PHC who was treated in our clinic. A total of 58 patients, including our one new case, (age range: 4 to 70 years, mean ± SD: 31.4 ± 15.9 years) were included in the analysis. Twenty-nine of the patients were female, and 29 were male. The information about cyst location was available from studies involving 54 patients and indicated the following distribution of locations: pancreatic head (n = 21), pancreatic tail (n = 18), pancreatic body and tail (n = 8), pancreatic body (n = 5), pancreatic head and body (n = 1), and pancreatic neck (n = 1). Extra-pancreatic locations of hydatid cysts were reported in the studies involving 44 of the patients. Among these, no other focus than pancreas was detected in 32 of the patients (isolated cases) while 12 of the patients had hydatid cysts in extra-pancreatic sites (liver: n = 6, liver + spleen + peritoneum: n = 2, kidney: n = 1, liver + kidney: n = 1, kidney + peritoneum: n = 1 and liver + lung: n = 1). Serological information was available in the studies involving 40 patients, and 21 of those patients were serologically positive and 15 were serologically negative; the remaining 4 patients underwent no serological testing. Information about pancreatic cyst size was available in the studies involving 42 patients; the smallest cyst diameter reported was 26 mm and the largest cyst diameter reported was 180 mm (mean ± SD: 71.3 ± 36.1 mm). Complications were available in the studies of 16 patients and showed the following distribution: cystobiliary fistula (n = 4), cysto-pancreatic fistula (n = 4), pancreatitis (n = 6), and portal hypertension (n = 2). Postoperative follow-up data were available in the studies involving 48 patients and postoperative recurrence data in the studies of 51 patients; no cases of recurrence occurred in any patient for an average follow-up duration of 22.5 ± 23.1 (range: 2-120) mo. Only two cases were reported as having died on fourth (our new case) and fifteenth days respectively. PHC is a parasitic infestation that is rare but can cause serious pancreato-biliary complications. Its preoperative diagnosis is challenging, as its radiologic findings are often mistaken for other cystic lesions of the pancreas.

GLP-1 Effects on Islets: Hormonal, Neuronal, or Paracrine?

According to the classical incretin concept, glucagon-like peptide (GLP)-1 is viewed as a hormone produced in the intestinal L cells and acting via the circulation on satiety in the brain, gut motility, and insulin and glucagon secretion in the pancreatic islet. However, in contrast to typical hormones, plasma levels of GLP-1 are relatively low with a very short half-life. Furthermore, GLP-1 is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) in the vicinity of L cells within <1 min from the secretion of the gut peptide (1,2). This rapid metabolism of GLP-1 raises questions about how its effects are mediated on target organs such as pancreatic β-cells. In this review, we will discuss possible alternative pathways for the incretin effect on pancreatic islet. These involve L cell–derived GLP-1 via neuronal activation and α-cell–derived GLP-1 via auto/paracrine effects. Of note, GLP-1 is not acting alone, and its effect can be modulated by other factors including GIP. Since no data are available yet in the present context, we have limited this review to GLP-1. ### GLP-1 in the gut-to-brain-to-periphery axis for the control of glucose metabolism Recent rodent data show that GLP-1 can induce its metabolic actions by interacting with its receptors in extrapancreatic locations such as the gut to activate the submucosal and the myenteric nervous plexi (3,4) and the brain, which then transmit the signal to peripheral tissues (5) within minutes from the absorption of glucose and lipids. The final aim of this axis is to anticipate the breakthrough of the nutrients into the blood and their better handling. Indeed, GLP-1 secreted from L cells can influence brain neuronal activities via an alternative neural pathway initiated by sensors in the hepatic portal region (6–8). Thereby, the vagus nerve transmits the metabolic information to the nucleus tractus solitarii in the brain stem, which relays the glucose signal to hypothalamic …

Topologically Heterogeneous Beta Cell Adaptation in Response to High-Fat Diet in Mice

AimsBeta cells adapt to an increased insulin demand by enhancing insulin secretion via increased beta cell function and/or increased beta cell number. While morphological and functional heterogeneity between individual islets exists, it is unknown whether regional differences in beta cell adaptation occur. Therefore we investigated beta cell adaptation throughout the pancreas in a model of high-fat diet (HFD)-induced insulin resistance in mice.MethodsC57BL/6J mice were fed a HFD to induce insulin resistance, or control diet for 6 weeks. The pancreas was divided in a duodenal (DR), gastric (GR) and splenic (SR) region and taken for either histology or islet isolation. The capacity of untreated islets from the three regions to adapt in an extrapancreatic location was assessed by transplantation under the kidney capsule of streptozotocin-treated mice.ResultsSR islets showed 70% increased beta cell proliferation after HFD, whereas no significant increase was found in DR and GR islets. Furthermore, isolated SR islets showed twofold enhanced glucose-induced insulin secretion after HFD, as compared with DR and GR islets. In contrast, transplantation of islets isolated from the three regions to an extrapancreatic location in diabetic mice led to a similar decrease in hyperglycemia and no difference in beta cell proliferation.ConclusionsHFD-induced insulin resistance leads to topologically heterogeneous beta cell adaptation and is most prominent in the splenic region of the pancreas. This topological heterogeneity in beta cell adaptation appears to result from extrinsic factors present in the islet microenvironment.

Lymphoepithelial cyst of the pancreas: comparison of CT findings with other pancreatic cystic lesions

To describe the CT findings of lymphoepithelial cysts (LECs) of the pancreas and to investigate the differential findings between LECs and other pancreatic cystic lesions. Fifty-eight patients with 8 LECs (M:F = 7:1; mean age 55.1 years), 30 serous cystadenomas (SCA) (M:F = 11:19; 52.5 years), 11 mucinous cystadenomas (MCA) (M:F = 0:11; 47.2 years), and 9 pseudocysts (M:F = 6:3; 50.8 years) were included in this study. Two radiologists analyzed all CT images for 3D location, outer shape, appearance, the presence of calcification, enhancing nodule, and pancreatic duct dilatation. Size of lesions and CT number of cystic portion on precontrast CT were measured. For statistical analysis, Mann-Whitney U test and Fisher's exact test were used. 75 % (6/8) of LECs showed an extrapancreatic location than all other cystic diseases in terms of 3D location (p < 0.0001). LECs showed variable outer shape without a significant difference from that of SCAs and pseudocysts (p > 0.05), but LECs showed microlobulated surface more frequently than the MCAs (p < 0.05). LECs showed a variable appearance from unilocular to multi-microcystic. CT attenuation of LECs (21.2 ± 7.1 HU) was higher than that of SCAs and MCAs (p = 0.005). Size of LECs (34.0 ± 10.8 mm) was smaller than that of MCAs (p = 0.040). There was no calcification, pancreatic duct dilatation, or enhancing nodules in LECs. LECs appear as a highly exophytic medium-sized cystic mass with various morphology occurring predominantly in the middle-aged or older male patients.

6604 Exploring the role of CA 19–9 level as a predictor of survival in patients with advanced pancreatic adenocarcinoma

Heterotopic pancreatic parenchyma recapitulates the normal pancreas in extrapancreatic locations and, on rare occasions, can even give rise to pancreatic adenocarcinoma. The genetic signatures of pancreatic adenocarcinoma and its precursor lesions are well characterized. We explored the genetic alterations in precursor lesions (intraductal papillary mucinous neoplasms [IPMN], pancreatic intraepithelial neoplasia [PanIN]) in patients with pancreatic heterotopias but without concomitant pancreatic ductal adenocarcinomas. This allowed us to determine whether the stereotypical dysplasia--infiltrating carcinoma sequence also occurs in these extrapancreatic foci. Seven cases of heterotopic pancreas with ductal precursor lesions were identified. These included 2 IPMNs with focal high-grade dysplasia and 5 PanINs with low- to moderate-grade dysplasia (PanIN grades 1-2). Neoplastic epithelium was microdissected and genomic DNA was extracted. Sequencing of commonly mutated hotspots (KRAS, TP53, CDKN2A, SMAD4, BRAF, and GNAS) in pancreatic ductal adenocarcinoma and its precursor lesions was performed. Both IPMNs were found to have KRAS codon 12 mutations. The identification of KRAS mutations suggests a genetic pathway shared with IPMN of the pancreas. No mutations were identified in our heterotopic PanINs. One of the possible mechanisms for the development of dysplasia in these lesions is field effect. At the time of these resections, there was no clinical or pathologic evidence of a prior or concomitant pancreatic lesion. However, a clinically undetectable lesion is theoretically possible. Therefore, although a field effect cannot be excluded, there was no evidence for it in this study.

Pancreatic pseudocyst located in the liver

Pancreatic pseudocyst is a common complication of acute and chronic pancreatitis. Extrapancreatic locations of pancreatic pseudocyst in the liver, pleura, mediastinum, or pelvis have been described. However, a pancreatic pseudocyst located in the liver is an infrequent condition. We present the case of a 46-year-old man with pancreatic pseudocyst located in the liver secondary to chronic alcoholic pancreatitis. During admission, the patient underwent an abdominal CT scan that showed a mass located in the head and body of the pancreas, as well as a thrombosis of the splenic vein. A percutaneous needle aspiration biopsy of the pancreas was obtained under CT guidance, which showed no tumoral involvement. Fourty-eight hours after the procedure the patient developed abdominal pain and elevated serum amylase levels. A pancreatic MRI exam showed two pancreatic pseudocysts, one of them located in the left hepatic lobe, the other in the pancreatic tail. Chronic pancreatitis signs also were found. Enteral nutrition via a nasojejunal tube was administered for two weeks. The disappearance of the pancreatic pseudocyst located in the pancreatic tail, and a subtotal resolution of the pancreatic pseudocyst located in the liver were observed. To date twenty-seven cases of pancreatic pseudocyst located in the liver have been published, most of them managed with percutaneous or surgical drainage.

Use of intraoperative ultrasonography to localize islet cell tumors.

Because approximately 50% of insulinomas and a similar proportion of gastrinomas are not evident on preoperative imaging studies, precise intraoperative localization of these small tumors is imperative. Recently the use of high-resolution real-time B-mode ultrasonography has dramatically facilitated the operative detection of pancreatic islet cell tumors. The tumor appears sonolucent compared to the more echo-dense surrounding pancreas. This operative technique has been especially useful in patients with insulinoma because these tumors are generally located within the pancreas. In fact, it is so helpful during explorations for insulinoma some suggest that extensive preoperative localization studies are no longer indicated--that the patient can simply be explored with intraoperative ultrasonography (IOUS). It has not been as useful for gastrinomas because of their common extrapancreatic location. Accumulating evidence suggests that IOUS is an effective tool to aid in the operative localization and resection of pancreatic islet cell tumors. Not only can it precisely localize the tumor, it can accurately document the relation of the tumor to other vital pancreatic structures including ducts, veins, and arteries.

Islet cell adenoma with hyperinsulinism

A brief review of the incidence, pathology, symptomatology and treatment of islet cell tumors is presented. The frequency of islet cell tumors is closely related to an awareness of the possible existence of such lesions in patients suffering from symptoms of hypoglycemia. Recognition of the Whipple triad serves as the key in diagnosis. In a patient exhibiting this triad in whom extrapancreatic factors have been ruled out surgery is indicated. Enucleation or resection is the procedure of choice when a tumor can be found either in the pancreas or in an heteroptopic extrapancreatic location. If careful search fails to reveal any evidence of an adenoma of the pancreas, adequate subtotal resection of the pancreas is recommended. A case report of the successful surgical removal of an islet cell adenoma of the pancreas is presented.