Intracholecystic papillary neoplasm arising in a patient with pancreaticobiliary maljunction: a case report.

BACKGROUND: Pancreaticobiliary maljunction (PBM) is a congenital abnormality in which the pancreatic and biliary ducts join anatomically outside the duodenal wall resulting in the regurgitation of pancreatic juice into the biliary tract (pancreatobiliary reflux). Persistent pancreatobiliary reflux causes injury to the epithelium of the biliary tract and promotes the risk of biliary cancer. Intracholecyctic papillary neoplasm (ICPN) has been highlighted in the context of a cholecystic counterpart of intraductal papillary mucinous neoplasm of the pancreas and the bile duct, but the tumorigenesis of ICPNs remains unclear. CASE PRESENTATION: A 52-year-old Japanese woman was referred for the assessment of dilation of the bile duct. Computed tomography which revealed an enhanced mass in the gallbladder and endoscopic retrograde cholangiopancreatography confirmed that the confluence of the main pancreatic duct and extrahepatic bile duct (EHBD) was located outside the duodenal wall. Under the diagnosis of gallbladder cancer with PBM, cholecystectomy with full thickness dissection, EHBD resection, lymph node dissection, and hepaticojejunostomy were performed. Macroscopic examination of the resected specimen showed that the cystic duct was dilated and joined into the EHBD just above its confluence with the pancreatic duct, and the inflamed change of non-tumorous mucosa of gallbladder indicating that there was considerable mucosal injury due to pancreatobiliary reflux to the gallbladder. Histopathological examination revealed that the gallbladder tumor was a gastric-type ICPN with non-invasive component. Either KRAS gene mutation or p53 protein expression that were known to be associated with the carcinogenesis of biliary cancer under the condition of pancreatobiliary reflux was not detected in the tumor cells of ICPN. CONCLUSION: The present case might suggest that there was no association between PBM and ICPN. To reveal the tumorigenesis of ICPN and its attribution to pancreatobiliary reflux, however, further study is warranted.

A case of mixed adenoneuroendocrine carcinoma of the gallbladder arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction.

A 54-year-old Japanese woman was referred with a gallbladder tumor. Based on the results of the computed tomography scan, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography, a mucin-producing neoplasm of the gallbladder associated with pancreaticobiliary maljunction was diagnosed. Extended cholecystectomy, extrahepatic bile duct resection, and choledochojejunostomy were performed, and she remains free of recurrence 24 months after resection. Histopathological examination revealed that the papillary component of the lesion was an intracystic papillary neoplasm with diverse characteristics of pancreaticobiliary epithelium and intestinal epithelium including mucin. In this component, most of the papillary lesion was a high-grade intraepithelial neoplasm, but also showed slight invasion into the muscular layer. The nodular component consisted of both poorly differentiated biliary type adenocarcinoma and large cell neuroendocrine carcinoma. We report a rare case of a mixed adenoneuroendocrine carcinoma arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. As for the histogenesis of this tumor, based on the histopathologic appearance, transdifferentiation from poorly differentiated biliary type adenocarcinoma to large cell neuroendocrine carcinoma is considered the most possible histogenesis of this tumor.

Incipient Intracholecystic Papillary Neoplasm of the Gallbladder Without Dysplasia.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a rare tumor described as a mucosal exophytic neoplastic lesion that projects into the gallbladder lumen. In regards to the size, lesions that did not make the arbitrary 1cm cutoff are described as "incipient" ICPN. Not much is known about these incipient ICPNs, as they are often excluded in ICPN studies, given the attempted adherence to the traditional 1cm cutoff. We present the youngest reported case of incipient, non-mucinous gastric-pylorus type ICPN who underwent cholecystectomy. Resection with negative margin for ICPN appears to be sufficient treatment and post resection imaging surveillance could be of value but further studies are required.

Dysplasia and Early Carcinoma of the Gallbladder and Bile Ducts: Terminology, Classification, and Significance.

Most precursor lesions and early cancerous changes in the gallbladder and bile ducts present as clinically/grossly inapparent lesions. Low-grade dysplasia is difficult to define and clinically inconsequential by itself; however, extra sampling is required to exclude accompanying significant lesions. For high-grade dysplasia ('carcinoma in situ'), a complete sampling is necessary to rule out invasion. Tumoral intramucosal neoplasms (ie, intracholecystic and intraductal neoplasia) form radiologically/grossly visible masses, and they account for (present in the background of) about 5% to 10% of invasive cancers of the region. These reveal a spectrum of papilla/tubule formation, cell lineages, and dysplastic transformation. Some subtypes such as intracholecystic tubular non-mucinous neoplasm of the gallbladder (almost never invasive) and intraductal oncocytic or intraductal tubulopapillary neoplasms of the bile ducts (may have a protracted clinical course even when invasive) are to be noted separately. Other types of intracholecystic/intraductal neoplasia have a high frequency of invasive carcinoma and progressive behavior, which often culminates in mortality.

TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern.

A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors' database. Among the 16 TPPP-BRD9 fusion-positive GBC cases, most were females (F:M = 7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p < 0.001), all with gastro-pancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC) morphology: 3 cases (27% vs. 4.6% in the reference database, p = 0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remaining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a "syringoid" appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubular-spindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC morphology and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.

Diagnostic usefulness of SpyGlass in intracholecystic papillary neoplasm with pancreaticobiliary maljunction: a case report and comparison with conventional gallbladder cancer with pancreaticobiliary maljunction.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is one of the precursors of gallbladder cancer defined in the 2010 World Health Organization classification of tumors. We herein report ICPN with pancreaticobiliary maljunction (PBM), which is a high-risk factor for biliary cancer. CASE PRESENTATION: A 57-year-old female presented with abdominal pain. Computed tomography showed a swollen appendix and gallbladder nodules with bile duct dilatation. Endoscopic ultrasonography revealed a gallbladder tumor spreading into the cystic duct confluence accompanying PBM. Based on papillary tumors around the cystic duct detected using the SpyGlass DS II Direct Visualization System (SpyGlass DS), ICPN was suspected. We performed extended cholecystectomy, extrahepatic bile duct resection, and appendectomy with a diagnosis of ICPN and PBM. The pathological diagnosis was ICPN (90 × 50 mm) with high-grade dysplasia spreading into the common bile duct. The absence of residual cancer in the resected specimen was pathologically confirmed. P53 staining was totally negative in both the tumor and normal epithelium. The overexpression of CTNNB1 was not observed. CONCLUSIONS: We encountered a patient with a very rare gallbladder tumor, ICPN with PBM. SpyGlass DS contributed to a precise assessment of the extent of the tumor as well as a qualitative diagnosis.

p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.

KRAS and TP53 mutations are frequently observed in extrahepatic biliary cancer. Mutations of KRAS and TP53 are independent risk factors for poor prognosis in biliary cancer. However, the exact role of p53 in the development of extrahepatic biliary cancer remains elusive. In this study, we found that simultaneous activation of Kras and inactivation of p53 induces biliary neoplasms that resemble human biliary intraepithelial neoplasia in the extrahepatic bile duct and intracholecystic papillary-tubular neoplasm in the gall bladder in mice. However, inactivation of p53 was not sufficient for the progression of biliary precancerous lesions into invasive cancer in the context of oncogenic Kras within the observation period. This was also the case in the context of additional activation of the Wnt signaling pathway. Thus, p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.

Conducting Polymer-Hydrogel Interpenetrating Networks for Improving the Electrode-Neural Interface.

Implantable neural microelectrodes are recognized as a bridge for information exchange between inner organisms and outer devices. Combined with novel modulation technologies such as optogenetics, it offers a highly precise methodology for the dissection of brain functions. However, achieving chronically effective and stable microelectrodes to explore the electrophysiological characteristics of specific neurons in free-behaving animals continually poses great challenges. To resolve this, poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)/poly(vinyl alcohol) (PEDOT/PSS/PVA) interpenetrating conducting polymer networks (ICPN) are fabricated via a hydrogel scaffold precoating and electrochemical polymerization process to improve the performance of neural microelectrodes. The ICPN films exhibit robust interfacial adhesion, a significantly lower electrochemical impedance, superior mechanical properties, and improved electrochemical stability compared to the pure poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)(PEDOT/PSS) films, which may be attributed to the three-dimensional (3D) porous microstructure of the ICPN. Hippocampal neurons and rat pheochromocytoma cells (PC12 cells) adhesion on ICPN and neurite outgrowth are observed, indicating enhanced biocompatibility. Furthermore, alleviated tissue response at the electrode-neural tissue interface and improved recording signal quality are confirmed by histological and electrophysiological studies, respectively. Owing to these merits, optogenetic modulations and electrophysiological recordings are performed in vivo, and an anxiolytic effect of hippocampal glutamatergic neurons on behavior is shown. This study demonstrates the effectiveness and advantages of ICPN-modified neural implants for in vivo applications.

The Clinical and Pathologic Features of Intracholecystic Papillary-Tubular Neoplasms of the Gallbladder.

Intracholecystic papillary-tubular neoplasm denotes a discrete mucosal-based neoplastic proliferation into the gallbladder lumen. It is diagnosed incidentally during cholecystectomy or radiologically during a workup for abdominal pain. The majority of polypoid lesions in the gallbladder are non-neoplastic; therefore, pathologic examination is the gold standard to establish this diagnosis. Intracholecystic papillary-tubular neoplasm is considered as premalignant, although associated invasive carcinomas may be present in the specimen. Invasive carcinoma arising from intracholecystic papillary-tubular neoplasm have a better prognosis than de novo gallbladder carcinomas. The pathology of intracholecystic papillary-tubular neoplasm, including the challenges involved in the diagnosis of this entity, is discussed.

Intracholecystic papillary neoplasm of the gallbladder diagnosed during follow-up of Menetrier's disease: A case report.

Intracholecystic papillary neoplasm of the gallbladder (ICPN) is a type of intraductal papillary neoplasm of the bile duct that occurs in the gallbladder, and is a relatively newer concept. Therefore, there are few reports regarding ICPN. Menetrier's disease is a rare disease characterized by giant hypertrophy of the gastric folds that causes protein-losing gastroenteropathy (PLG). Although Menetrier's disease is a known risk factor for gastric adenocarcinoma, the association between Menetrier's disease and malignancy other than a malignancy of the stomach is unclear. A 69-year-old man presented to the Hokkaido Social Work Association Obihiro Hospital with gallbladder tumours diagnosed by ultrasonography at a previous institution. In addition, he had previously been diagnosed with PLG due to Menetrier's disease. Abdominal contrast-enhanced computed tomography (CT) revealed an irregular mass with a contrast effect at the fundus of the gallbladder on the free abdominal cavity side. Positron emission tomography-CT showed a tumour with a standard uptake value (SUV) of 8.28 at the fundus of the gallbladder. Cholecystectomy and resection of the gallbladder bed were performed. Based on the microscopy findings, the patient was diagnosed with ICPN. Although he had postoperative ileus, he was discharged 14 days postoperatively due to improvement through conservative treatment. Such cases of ICPN complicated with Menetrier's disease are extremely rare. However, patients with Menetrier's disease may need to be screened for malignancies.

Intracholecystic papillary neoplasm arising in the cystic duct and extending into common bile duct: a case report.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

Intracholecystic papillary-tubular neoplasm of the gallbladder originating in the cystic duct with extensive intraepithelial progress in the common bile duct.

A 59-year-old man with anorexia who had a history of cholecystectomy was referred to our hospital. Imaging examinations revealed a contrast-enhanced tumor in the residual cystic duct and a part of the common bile duct. Endoscopic retrograde cholangiopancreatography and peroral-cholangioscopy showed a papillary tumor with movement and a change in the shape. Under a diagnosis of primary cystic duct cancer, subtotal stomach-preserving pancreaticoduodenectomy was performed. The microscopic examination of a resected specimen revealed intracholecystic papillary-tubular neoplasm located in the residual cystic duct, forming a polypoid protrusion to the common bile duct and extensive intraepithelial progress in the common bile duct.

Three cases of intracystic papillary neoplasm of gallbladder.

Intracystic papillary neoplasm (ICPN) of gallbladder is a comparatively new concept and is described as pre-malignant lesions in Nakanuma et al. (In: Bosman et al. (eds) WHO Classification of Tumours of the Digestive System, World Health Organization of Tumours, IARC, Lyon, 2010). ICPN with high-grade intraepithelial neoplasia is understood to include intraepithelial carcinoma or noninvasive carcinoma. And lesions with invasive cancer components are classified as ICPN with an associated invasive carcinoma [1]. According to Adsay et al., more than half of patients diagnosed with ICPN have invasive cancer components (Adsay et al., Am J Surg Pathol 36:1279-1301, 2012).Polypoid masses in the gallbladder including benign, malignant, and non-neoplastic lesions have been called gallbladder polyps, and ICPN is also a polypoid lesion in the gallbladder. However, it is difficult to differentiate between them. In the literature, it is said that the possibility of malignancy is high in lesions exceeding 1 cm (Terzi et al., Surgery 127:622-627, 2000). And there are few reports on characteristic imaging findings of ICPN.We have experienced three cases (two females and one male) of ICPN and report our imaging findings. Contrast-enhanced computed tomography revealed large papillary polypoid lesions approximately 2-4 cm in size in the gallbladder. Findings suggestive of deformation of the gallbladder wall and extrinsic progression were absent in all cases. T2-weighted magnetic resonance imaging revealed intense signals and diffusion-weighted imaging showed high intensity. Expanding of the gallbladder was seen in case 1, and a tumor stalk-like appearance was seen in the papillary mass in cases 2 and 3. Surgery was performed in all three cases and ICPN was diagnosed pathologically. The cancer was localized to the mucosa, with no infiltration of surrounding tissue in all three cases.

Neoplasia papilar intracolecística: reporte de un caso y revisión de la evidencia existente / Intracholecystic papillary neoplasia: report of a case and review of existing evidence

La neoplasia papilar intracolecística (NPIC), es un tumor compuesto por células neoplásicas preinvasivas, que forman masas de hasta 1,0 cm, clínicamente detectables. El objetivo de este estudio fue reportar un caso de NPIC y revisar la evidencia existente. Se trata de un paciente sexo masculino, de 33 años de edad, asintomático, que en el curso de un examen de salud, se realiza una ecotomografía abdominal, en la que se verifica una lesión polipoide vesicular de 32 x 19 mm de diámetro. Se programa para colecistectomía electiva, la que se realizó por vía laparoscópica, cirugía que se pudo realizar sin inconvenientes. Una vez extirpado el espécimen, se fue a estudio histopatológico en el que tras un mapeo vesicular se concluye NPIC, colecistitis crónica inespecífica, colesterolosis y pólipos colesterínicos. El paciente ha evolucionado sin inconvenientes. Presentamos un caso de NPIC en un paciente joven, cuyo diagnóstico fue confirmado por anatomía patológica tras una colecistectomía electiva, descartándose la presencia de carcinoma invasivo y displasia de alto grado, por lo que el pronóstico es favorable.

Intracholecystic papillary neoplasm (ICPN) is a tumor composed of pre-invasive neoplastic cells, with up to 1.0 cm clinically detectable masses. The objective of this study was to report a case of NPIC and review the evidence in the literature. A 33-year-old asymptomatic male patient had an abdominal ultrasonography during a health examination, in which a vesicular polyp lesion of 32 x 19 mm in diameter was verified. Thepatient was subsequently scheduled for elective cholecystectomy, which was performed laparoscopically and the surgery was uneventful. Once removed, the specimen was studied histopathologically and after performing vesicular mapping, we determined an ICPN, chronic non-specific cholecystitis, cholesteroliasis and cholesteric polyps. The patient has evolved without reported problems. We present a case of ICPN in a young patient, whose diagnosis was confirmed by pathological anatomy after an elective cholecystectomy, ruling out the presence of invasive carcinoma and high-grade dysplasia, with a favorable prognosis.