Biliary Tract Epithelium Research Articles

Intrahepatic Cholangiocarcinoma Presenting as an Incidentaloma on F-18 PYL PSMA PET/CT

AbstractCholangiocarcinoma is an aggressive malignancy arising from the biliary tract epithelium with rising incidence and mortality. Imaging commonly used for diagnostic workup includes computed tomography (CT) scan and magnetic resonance imaging (MRI). Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) scans can be used for investigating equivocal findings on radiographic imaging. Prostate-specific membrane antigen (PSMA) is known to be highly expressed in prostate adenocarcinoma, allowing it to be leveraged as a target for both imaging and radioligand therapy in prostate cancer. However, PSMA is also commonly expressed in other malignancies such as breast cancer, thyroid carcinomas, and head and neck malignancies, which increase the chances of their incidental diagnosis on PSMA PET scans. Biliary tract cancers, including cholangiocarcinoma, are not commonly expected to be incidentally diagnosed on PSMA PET imaging. Here, we describe the case of a patient with known prostate adenocarcinoma who was later incidentally diagnosed with advanced intrahepatic cholangiocarcinoma on PSMA PET/computed tomography (CT). This case highlights the unexpected finding of cholangiocarcinoma on PSMA PET/CT and suggests further investigation into the role of PSMA PET in diagnosing ambiguous cases of cholangiocarcinoma and its potential theranostic applications.

Characterization of a Syngeneic Orthotopic Model of Cholangiocarcinoma by [18F]FDG-PET/MRI.

Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [18F]FDG-PET, and dynamic [18F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies.

A New Era for Cholangiocarcinoma Therapy – Targeting Metabolic Enzymes

Cholangiocarcinoma (CCA) is a malignancy of the biliary tract epithelium and is the second most common primary liver tumor following hepatocellular carcinoma (HCC): it accounts for ~15% of primary liver cancers and ~3% of gastrointestinal malignancies. Due to late diagnoses, poor prognoses, and limited treatment strategies, CCA shows a dismal outcome with a less than 5% overall 5-year survival and only a median overall survival of ~7months. Moreover, epidemiological data show that the incidence (0.3–6 per 100,000) and mortality (1 -6 per 100,000) of CCA is increasing globally over recent decades. Cholangiocarcinoma (CCA) is associated with approximately 3,500 new cases, the second most common primary liver tumor in Germany. Cholangiocarcinoma (CCA) is classified into anatomic subtypes including intrahepatic CCA (iCCA), perihilar CCA (pCCA) and extrahepatic CCA (eCCA).

Cirrhosis in intrahepatic cholangiocarcinoma: prognostic importance and impact on survival

ContextCholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium is of increasing importance due to its rising incidence worldwide. There is a lack of data on cirrhosis in intrahepatic CCA (iCCA) and how it affects overall survival and prognosis.ObjectivesThe primary objective of this study was to examine if there were differences in survival outcomes between iCCA patients with concomitant cirrhosis and those without cirrhosis.MethodsThe National Cancer Database (NCDB) was used to identify and study patients with iCCA from 2004 to 2017. The presence of cirrhosis was defined using CS Site-Specific Factor 2 where 000 indicated no cirrhosis and 001 indicated the presence of cirrhosis. Descriptive statistics were utilized for patient demographics, disease staging, tumor, and treatment characteristics. Kaplan-Meier (KM) method with log-rank test and a multivariate logistic regression model was used to assess if the presence of cirrhosis in iCCA was associated with survival status and long-term survival (60 or more months after diagnosis).ResultsThere were 33,160 patients with CCA in NCDB (2004–2017), of which 3644 patients were diagnosed with iCCA. One thousand fifty-two patients (28.9%) had cirrhosis as defined by Ishak Fibrosis score 5–6 on biopsy and 2592 patients (71.1%) did not meet the definition for cirrhosis. Although in univariate analyses using KM/log-rank tests showed a survival advantage for non-cirrhotic patients, there was no statistically significant association found between cirrhosis and survival status (OR = 0.82, p = 0.405) or long-term survival (OR = 0.98, p = 0.933) when multivariate analysis was used. iCCA patients with cirrhosis and Stage 1 tumor had the highest median OS (132 months) vs 73.7 months in the non-cirrhotic arm, while patients with stage IV disease who had cirrhosis had half the survival time of those without. Our data thus indicates that the presence of cirrhosis is not an independent prognostic factor for survival.

Diagnosis of Indolent Clonorchis sinensis and Opisthorchis viverrini Infections as Risk Factors for Cholangiocarcinoma: An Unmet Medical Need.

Cholangiocarcinoma is a highly aggressive cancer of the biliary tract epithelium. This form of cancer is prevalent in Asia, and recent reports show that its incidence is relatively rare but increasing in the United States. Although risk factors for cholangiocarcinoma have yet to be elucidated, a growing body of literature suggests chronic infection of genetically susceptible individuals with the food-borne zoonotic trematodes Clonorchis sinensis (C sinensis) and Opisthorchis viverrini (O viverrini) may play a role. Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for almost 30 years. During this period, the trematodes' feeding activities and their excretory-secretory products may damage the bile duct epithelium and promote local inflammation. These pathological processes could then provoke epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to the initiation and progression of cholangiocarcinoma in genetically susceptible people. The International Agency for Research on Cancer has determined that there is sufficient evidence in humans for the carcinogenicity of chronic infections with C sinensis and O viverrini. Timely serodiagnosis of indolent C sinensis and O viverrini infections is important as these parasites may be a risk factor for cholangiocarcinoma in veterans who served in Vietnam. About 774,000 living Americans served in Vietnam and there is an urgent need to develop sensitive and specific serologic assays to detect both acute and indolent infections. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival.

Heterogeneity of Cholangiocarcinoma Immune Biology

Cholangiocarcinomas (CCAs) are aggressive tumors arising along the biliary tract epithelium, whose incidence and mortality are increasing. CCAs are highly desmoplastic cancers characterized by a dense tumor microenvironment (TME), in which each single component plays a fundamental role in shaping CCA initiation, progression and resistance to therapies. The crosstalk between cancer cells and TME can affect the recruitment, infiltration and differentiation of immune cells. According to the stage of the disease and to intra- and inter-patient heterogeneity, TME may contribute to either protumoral or antitumoral activities. Therefore, a better understanding of the effect of each immune cell subtype may open the path to new personalized immune therapeutic strategies for the management of CCA. In this review, we describe the role of immune cells in CCA initiation and progression, and their crosstalk with both cancer-associated fibroblasts (CAFs) and the cancer-stem-cell-like (CSC) niche.

Carcinogenic risk in the biliary epithelium of children with congenital biliary dilatation via the DNA damage repair pathway.

Congenital biliary dilatation (CBD) is a high-risk factor for biliary tract cancer (BTC). We previously reported the potential for carcinogenesis in the biliary epithelium of patients with CBD. In this study, we investigated potential carcinogenetic pathways, focusing on the DNA damage repair response, in children with CBD and compared the findings with those in adults. We enrolled 6 children with CBD and 10 adults with CBD without BTC who underwent extrahepatic bile duct resections, plus 4 control patients who underwent pancreaticoduodenectomy for non-biliary cancer. Levels of phosphorylated histone H2AX (γH2AX), MRE11, and Ku-70 in the biliary tract epithelium were evaluated by immunohistochemistry. The levels of γH2AX, MRE11, and Ku-70 were significantly higher in the gallbladder epithelium and bile duct epithelium of both children and adults than in controls. Children and adults with CBD might develop BTC via the DNA damage repair pathway, as evidenced by increased γH2AX, MRE11, and Ku-70 expression.

Establishment and Characterization of a New Human Intrahepatic Cholangiocarcinoma Cell Line LIV27.

Simple SummaryCholangiocarcinoma (CCA) is usually diagnosed at a late stage and has a poor prognosis. Cell lines serve as useful models for testing scientific questions in vitro and in vivo. To aid scientific discovery for the purpose of improved early detection and treatment, we developed a CCA cell line, designated LIV27, from a surgically resected intrahepatic CCA in a Caucasian patient with primary sclerosing cholangitis (PSC). LIV27 has high tumorigenicity in nude mice and expands the availability of intrahepatic CCA cell lines.Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this study, we report and characterize a new intrahepatic CCA cell line, LIV27, derived from a surgically resected tumor in a 67-year-old Caucasian woman with primary sclerosing cholangitis (PSC). LIV27 cells grow well in collagen-coated flasks or plates with a doubling time of 57.8 h at passage 14. LIV27 cells have high tumorigenicity in nude mice and stain positive for CK7 and CK19, markers that differentiate CCA from hepatocellular carcinoma. Karyotype analysis showed that LIV27 is aneuploid. We established a single-locus short tandem repeat profile for the LIV27 cell line. This newly established cell line will be a useful model for studying the molecular pathogenesis of, and developing novel therapies for, cholangiocarcinoma.

SYNCHRONOUS AND METACHRONOUS TUMORS OF THE BILIARY TREE.

Biliary tract cancers arise in the biliary tract epithelium and include intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal extrahepatic cholangiocarcinoma, and gallbladder cancer. These sites are anatomically contiguous and may appear related, but they are heterogeneous with distinct genetic and molecular signatures. Cholangiocarcinoma is the malignant tumor arising from the epithelium of the biliary tract, first histologically described by Durand-Fardel in 1840. Classification as originating from the intra- and extrahepatic biliary epithelium1 is a common way of classifying these tumors as prognosis and behavior are different in both types. Extrahepatic cholangiocarcinomas are further separated like the Bismuth classification; into upper-third or perihilar (including the confluence of the right and left biliary ducts) tumors; middle-third tumors; and distal bile duct tumors. Performance of a marginnegative resection with regional lymphadenectomy remains the cornerstone of successful treatment of cholangipcarcinoma.

Extrahepatic cholangiocarcinoma versus intrahepatic cholangiocarcinoma: A comparison of survival outcomes and use of palliative care in diagnosed patients.

e16192 Background: Cholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium, is of increasing importance due to its rising incidence worldwide. However, it also remains one of the most lethal malignances with a survival rate ranging between 6-16 months. Despite poor outcomes, palliative care remains underutilized in CCA. Determining outcomes, and differences in various CCA types remains crucial in helping patients and clinicians make goal of care decisions with regards to aggressive treatment. Objectives:The objective of this study is to compare survival outcomes between intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA). In addition, it aims to compare the utilization palliative care in either subtype, considering the high morbidity and mortality of the disease. Methods: Pooled cross-sectional observational study of the2004-2017 National Cancer Database (NCDB), which contains almost 400,000 records. The study population included de-identified records of patients with CCA; ages 18-90. Descriptive statistics (frequency, means, and standard deviations) were used. For survival analyses, the Kaplan-Meier method with log-rank test and a multivariate Cox regression model was used. Results: A total of 53,054 patients with CCA were identified. Of which, 63.4% had iCCA and 36.7% of patients had eCCA. There were statistically significant differences between the two cohorts in regard to sex, race/ethnicity, as well as in Charlson Co-Morbidity score. 65.2% of iCCA patients had advanced clinical stages III/IV as compared to 62.5% of eCCA patients. Higher percentage of iCCA patients had bone metastasis (7.8% vs 4.6 %, p < 0.001), pulmonary metastasis (11.5% vs 7.8%; p <0.001) and tumor size greater than 5 cm (62.1% vs 20.7%, p <0.001) compared to eCCA. Regarding treatment, patients with iCCA were more likely to receive multi-agent chemotherapy (35.0% vs 26.2 %, p<0.001). Although statistically significant differences for primary site surgical intervention (25.5% vs 25.0%, p<0.001), as well as for immunotherapy (6% vs 5.4%, p= 0.048), was found, they were not clinically significant. Patients with eCCA had a higher 90-day mortality (11.4% vs 8.2%, p <0.001), with 21% less likelihood of survival compared to iCCA patients (AOR:0.79, CI:0.74-0.84). Palliative care remained underutilized, with a lower utilization in iCCA (15.7% vs 12.5%, p <0.001). Conclusions: Our study demonstrated that iCCA patients have better survival outcomes compared to eCCA patients. This could be due to biological/genomic differences which warrant future investigation. Future clinical trials could also stratify for the location of CCA. Despite CCA’s poor prognosis, palliative care remained underutilized, with lower utilization rates in iCCA compared to eCCA.

Prognostic and Predictive Molecular Markers in Cholangiocarcinoma.

Simple SummaryCholangiocarcinoma (CCA) is a heterogenous and aggressive malignancy of the intra- and extrahepatic biliary tract, marked by a steeply rising incidence on a global scale. While surgery remains the only curative treatment option, most patients present with advanced or unresectable disease, and are, therefore, treated with systemic therapy, albeit with limited benefit. Biomarkers obtained from either the patients’ serum or tumor tissue might facilitate therapy guidance by selecting patients who would benefit the most from surgical and adjuvant treatment strategies, as well as by identifying those with higher risk of disease recurrence. Furthermore, several genetic aberrations in CCA have been linked with improved response upon targeted therapies, thus highlighting their role as predictive biomarkers. In this review we provide an overview of currently known prognostic and predictive biomarkers and discuss their role in CCA.Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.

Risk of carcinogenesis in the biliary epithelium of children with congenital biliary dilatation through epigenetic and genetic regulation.

Congenital biliary dilatation (CBD), defined as pancreaticobiliary maljunction (PBM) with biliary dilatation, is a high risk factor for biliary tract cancer (BTC). KRAS and p53 mutations reportedly affect this process, but the mechanisms are unclear, as is the likelihood of BTC later in life in children with CBD. We investigated potential carcinogenetic pathways in children with CBD compared with adults. The subjects of this study were nine children with CBD and 13 adults with PBM (10 dilated, 3 non-dilated) without BTC who underwent extrahepatic bile duct resections, as well as four control patients who underwent pancreaticoduodenectomy for non-biliary cancer. We evaluated expressions of Ki-67, KRAS, p53, histone deacetylase (HDAC) and activation-induced cytidine deaminase (AID) in the biliary tract epithelium immunohistochemically. The Ki-67 labeling index (LI) and expressions of KRAS, p53, HDAC, and AID in the gallbladder epithelium were significantly higher or tended to be higher in both the children with CBD and the adults with PBM than in the controls. BTC may develop later in children with CBD and in adults with PBM, via HDAC and AID expression and through epigenetic and genetic regulation.

Inhibition of T-cell-mediated immune response via the PD-1/ PD-L1 axis in cholangiocarcinoma cells

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8+ T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-γ), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-γ increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-γ treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-γ-induced PD-L1 expression. After 48 h co-incubation, CD8+ T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-γ further increased CD8+ T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-L1/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients; however, further in vivo and clinical studies are required.

Advillin is a tuft cell marker in the mouse alimentary tract

Tuft cells are a rare population of chemosensory cells at the mucosal surface epithelia of hollow organs. Their name-giving morphological feature is an apical tuft of stiff microvilli. Accordingly, the actin-binding protein, villin, was identified as one of the first tuft cell markers in immunohistochemical analysis. Unfortunately, villin expression is not restricted to tuft cells, but is also prominent e.g. in enterocytes, which limits the use of this gene as a marker and as an experimental tool to genetically target tuft cells. Here, we report that the villin-related protein, advillin, is a specific tuft cell marker in the gastro-intestinal and biliary tract epithelia. In situ hybridization and immunohistochemistry revealed that advillin expression, unlike villin, was restricted to solitary cholinergic tuft cells in the mucosal linings of the small and large intestine, and in the gall bladder. In the glandular stomach, villin and advillin mRNA were present in all epithelial cells, while detectable protein levels were confined to solitary tuft cells. Advillin expression was no longer detectable in the mucosa of the intestinal and biliary tract from Pou2f3 deficient mice that lack tuft cells. Finally, crossing Avil-Cre transgenic mice with a double-fluorescent reporter mouse line resulted in specific targeting of gastro-intestinal and biliary tuft cells. Our analysis introduces advillin as a selective marker and tool in histological and functional analysis of the alimentary tract tuft cell system.

Cholangiocarcinoma as an Indication for Liver Transplantation in the Era of Transplant Oncology.

Cholangiocarcinoma (CCA) arises from the biliary tract epithelium and accounts for 10–15% of all hepatobiliary malignancies. Depending on anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA). The best treatment option for pCCA is liver resection and when a radical oncological surgery is obtained, 5-year survival rate are around 20–40%. In unresectable patients, following a specific protocol, liver transplantation (LT) for pCCA showed excellent long-term disease-free survival rates. Fewer data are available for iCCA in LT setting. Nevertheless, patients with very early unresectable iCCA appear to achieve excellent outcomes after LT. This review aims to evaluate existing evidence to define the current role of LT in the management of patients with CCA.

Advances in the Diagnosis and Treatment of Patients with Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) that arises from the biliary tract epithelium distal to the secondary biliary radicals. Over the past decade, significant advances have been made in the diagnosis, staging, and treatment of ICC. Emerging data have highlighted the importance of lymphadenectomy for elucidating patient prognosis as well as the at-risk nodal basins based on tumor location (de Jong et al. in J Clin Oncol 29(23):3140-3145, 2011). Several large randomized controlled trials have recently been published clarifying the role of adjuvant therapy for BTCs (Cloyd and Pawlik in J Oncol Pract 14(12):723-724, 2018). In addition, the molecular understanding of ICC pathogenesis has increased over time, leading to new potential molecular biomarkers and opening opportunities for novel targeted and immunologic therapies (Rizvi et al. in Nat Rev Clin Oncol 15(2):95-111, 2018). These recent advances serve to only improve our understanding of the optimal multidisciplinary treatment of this difficult disease.

Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules

Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody therapy is unknown, and knowledge of its tumor immune microenvironment is limited. We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma and assess functional effects of targeting checkpoint molecules on TILs. We isolated TILs from resected tumors of patients with cholangiocarcinoma and investigated their compositions compared with their counterparts in tumor-free liver (TFL) tissues and blood, by flow cytometry and immunohistochemistry. We measured expression of immune co-stimulatory and co-inhibitory molecules on TILs, and determined whether targeting these molecules improved ex vivo functions of TILs. Proportions of cytotoxic T cells and natural killer cells were decreased, whereas regulatory T cells were increased in tumors compared with TFL. While regulatory T cells accumulated in tumors, the majority of cytotoxic and helper T cells were sequestered at tumor margins, and natural killer cells were excluded from the tumors. The co-stimulatory receptor GITR and co-inhibitory receptors PD1 and CTLA4 were over-expressed on tumor-infiltrating T cells compared with T cells in TFL and blood. Antagonistic targeting of PD1 or CTLA4 or agonistic targeting of GITR enhanced effector molecule production and T cell proliferation in ex vivo stimulation of TILs derived from cholangiocarcinoma. The inter-individual variations in TIL responses to checkpoint treatments were correlated with differences in TIL immune phenotype. Decreased numbers of cytotoxic immune cells and increased numbers of suppressor T cells that over-express co-inhibitory receptors suggest that the tumor microenvironment in cholangiocarcinoma is immunosuppressive. Targeting GITR, PD1 or CTLA4 enhances effector functions of tumor-infiltrating T cells, indicating that these molecules are potential immunotherapeutic targets for patients with cholangiocarcinoma. The defense functions of immune cells are suppressed in cholangiocarcinoma tumors. Stimulating or blocking "immune checkpoint" molecules expressed on tumor-infiltrating T cells can enhance the defense functions of these cells. Therefore, these molecules may be promising targets for therapeutic stimulation of immune cells to eradicate the tumors and prevent cancer recurrence in patients with cholangiocarcinoma.

MiRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a lethal malignancy originating from the biliary tract epithelium. Most patients are diagnosed at an advanced stage. Even after resection with curative intent, prognosis remains poor. Previous studies have reported the evolving role of miRNAs as novel biomarkers in cancer diagnosis, prognostication and chemotherapy response. Various miRNAs, such as miR-21, miR-26, miR-122 and miR-150, have been identified as possible blood-based biomarkers for noninvasive diagnosis of CCA. Moreover, epithelial-mesenchymal transition(EMT)- and angiogenesis-associated miRNAs have been implicated in tumor cell dissemination and are able to determine clinical outcome. In fact, miRNAs involved in cell survival might even determine chemotherapy response. This review provides an overview of known miRNAs as CCA-specific biomarkers.

Current controversies in cholangiocarcinoma

Cholangiocarcinoma represents 10% of primary liver malignancies and accounts for less than 3% of all gastrointestinal malignant tumors, with an enormous geographical variation. This neoplasia can arise from the biliary tract epithelium or hepatic progenitor cells. Depending on the anatomic localization, it is classified into three subtypes: intrahepatic, perihilar and distal. This fact is one of the main difficulties, because there are many studies that indistinctly include the results in the management of these different types of cholangiocarcinoma, without differentiating its location and even including gallbladder cancer.There are many controversial points in epidemiology, liver transplantation as a treatment, limitations of different results by group and type of treatment, histological testing and chemotherapy. This is a narrative review about topics in cholangiocarcinoma. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

High expression of karyopherin-α2 and stathmin 1 is associated with proliferation potency and transformation in the bile duct and gall bladder epithelia in the cases of pancreaticobiliary maljunction.

Pancreaticobiliary maljunction (PBM) may be associated with an increased frequency of gall bladder cancer with no bile duct dilation. Karyopherin-α2 (KPNA2) and stathmin 1 (STMN1) were reported to play important roles in carcinogenesis and cancer progression. Fifteen patients with PBM who underwent surgical resection between 1999 and 2014 were included in this study. Using immunohistochemistry, we investigated the expression of p53, Ki-67, KPNA2, and STMN1 in normal biliary tract epithelium, hyperplastic epithelium, and cholangiocarcinoma (CC) tissues. Nuclear expression of KPNA2, p53, and Ki-67 expression was detected in hyperplastic epithelium and CC tissues. High KPNA2 expression was significantly associated with gender (P = 0.04), p53 nuclear accumulation (P = 0.00435), and Ki-67 expression (P = 0.0443) in the gall bladder and bile duct of PBM. On the other hand, STMN1 was only expressed in CC tissues and was not observed in normal bile duct and hyperplastic epithelia. KPNA2 might be a useful marker of hyperplasia, dysplasia, and carcinogenicity in patients with PBM. STMN1 evaluation might be a cancer-specific marker for CC patients with PBM similar as that for other cancers. J. Surg. Oncol. 2016;114:462-468. © 2016 Wiley Periodicals, Inc.