Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20-30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.

We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.

Intrahepatic cholangiocarcinoma is a highly lethal malignancy characterized by lymph node metastasis. This study aimed to evaluate the efficacy of indocyanine green fluorescence for visualization of lymphatic drainage and to assess its clinical application during laparoscopic lymph node dissection for intrahepatic cholangiocarcinoma.

All patients with intrahepatic cholangiocarcinoma who underwent laparoscopic left hepatectomy and lymph node dissection between October 2018 and January 2021 were reviewed. The patients were assigned to the indocyanine green group or non-intrahepatic cholangiocarcinoma group based on the staining technique used.

Of 38 patients with left hemiliver intrahepatic cholangiocarcinoma, 20 underwent intrahepatic cholangiocarcinoma tracer-guided laparoscopic radical left hepatectomy; 12 procedures were successful (indocyanine green group). During the same period, 18 patients were treated with traditional laparoscopic resection (control group). Their intraoperative factors were comparable and there were no differences in the incidence or severity of their postoperative complications 30 days after surgery (P > .05). In the indocyanine green group, more lymph nodes were harvested (mean [range]: 7.0 [6.0-8.0] vs 3.5 [3.0-5.0], P < .001) and the proportion of confirmed pathologic lymph nodes was higher (75.0%, 66.7%-87.5% vs 40%, 33.3%-50.0%, P < .001). ICG staining was observed in all (12/12, 100%) patients in the intrahepatic cholangiocarcinoma group at stations 8 and 12, and 9 (9/12, 75%) and 10 (11/12, 91.7%) patients at Stations 13 and 7, respectively.

The indocyanine green fluorescence imaging system is feasible, safe, and effective for tracing lymph nodes. It can be used to identify regional lymphatic drainage patterns and help define the scope of lymph node dissection in patients with intrahepatic cholangiocarcinoma.

Introduction: Cholangiocarcinoma (CCA) is a malignancy which arises from the biliary epithelium. Carcinogenesis of CCA is mainly linked to aberrant glucose metabolism and creation of an immunosuppressive environment around normal biliary epithelium. The incidence of CCA is higher in the East due to Opisthorchis viverrini, an endemic liver fluke. CCA has also be attributed to genetic, metabolic, and lifestyle risk factors.Areas covered: Differences in epidemiological risk factors are associated with varying phenotypes of CCA. Metabolic risk factors include diabetes, obesity, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome. Inherited metabolic risk factors include Wilson's disease and hemochromatosis. Metabolic disease is associated with a higher risk of CCA, with higher risk for the intrahepatic form. In this review, the authors provide an overview of available evidence regarding metabolic conditions associated with the development of CCA.Expert opinion: Metabolic disease is associated with a higher risk of intrahepatic CCA compared to its extrahepatic or hilar counterpart. As rates of obesity and metabolic syndrome increase, particularly in the West, it is conceivable that the incidence of CCA will also rise in the next years.

Allogenic red blood cell transfusions exert a potential detrimental effect on the survival when delivered to cancer patients undergoing surgery with curative intent. We performed a systematic review and meta-analysis to assess the association between perioperative allogenic red blood cell transfusions and risk of death as well as relapse after surgery for localized solid tumors. PubMed, the Cochrane Library, and EMBASE were searched from inception to March 2019 for studies reporting the outcome of patients receiving transfusions during radical surgery for non-metastatic cancer. Risk of death and relapse were pooled to provide an adjusted hazard ratio with a 95% confidence interval [hazard ratio (HR) (95% confidence interval {CI})]. Mortality and relapse associated with perioperative transfusion due to cancer surgery were evaluated among participants (n = 123 studies). Overall, RBC transfusions were associated with an increased risk of death [HR = 1.50 (95% CI 1.42-1.57), p < 0.01] and relapse [HR = 1.36 (95% CI 1.26-1.46), p < 0.01]. The survival was reduced even in cancer at early stages [HR = 1.45 (1.36-1.55), p < 0.01]. In cancer patients undergoing surgery, red blood cell transfusions reduced the survival and increased the risk of relapse. Transfusions based on patients' blood management policy should be performed by applying a more restrictive policy, and the planned preoperative administration of iron, if necessary, should be pursued.

Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co-occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide.

Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent primary liver neoplasm after hepatocellular carcinoma (HCC), corresponding to 10% to 15% of cases. Pathologies that cause chronic biliary inflammation and bile stasis are known predisposing factors for development of ICC. The incidence and cancer-related mortality of ICC is increasing worldwide. Most patients remain asymptomatic until advance stage, commonly presenting with a liver mass incidentally diagnosed. The only potentially curative treatment available for ICC is surgical resection. The prognosis is dismal for unresectable cases. The principle of the surgical approach is a margin negative hepatic resection with preservation of adequate liver remnant. Regional lymphadenectomy is recommended at time of hepatectomy due to the massive impact on outcomes caused by lymph node (LN) metastasis. Multicentric disease, tumor size, margin status and tumor differentiation are also important prognostic factors. Staging laparoscopy is warranted in high-risk patients to avoid unnecessary laparotomy. Exceedingly complex surgical procedures, such as major vascular, extrahepatic bile ducts and visceral resections, ex vivo hepatectomy and autotransplantation, should be implemented in properly selected patients to achieve negative margins. Neoadjuvant therapy may be used in initially unresectable lesions in order to downstage and allow resection. Despite optimal surgical management, recurrence is frustratingly high. Adjuvant chemotherapy with radiation associated with locoregional treatments should be considered in cases with unfavorable prognostic factors. Selected patients may undergo re-resection of tumor recurrence. Despite the historically poor outcomes of liver transplantation for ICC, highly selected patients with unresectable disease, especially those with adequate response to neoadjuvant therapy, may be offered transplant. In this article, we reviewed the current literature in order to highlight the most recent advances and recommendations for the surgical treatment of this aggressive malignancy.

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy arising from biliary tract epithelium within bile ducts proximal to the secondary biliary radicles. The majority of patients are diagnosed with locally advanced or metastatic disease at presentation. Surgical resection remains the only potentially curative option, but poses unique challenges due to the large size and aggressive behavior of these tumors. Areas covered: The goal of surgical management of iCCA is margin negative (R0) hepatic resection with preservation of adequate size liver remnant and function. Data regarding role of staging laparoscopy, margin status, portal lymphadenectomy, and vascular resection for iCCA are reviewed. Perioperative systemic therapy may have value, although prospective data have been lacking. Recurrence rates remain high even after R0 resection; among patients with recurrent disease limited to the liver, re-resection or locoregional therapies may play a role. Liver transplantation may be an option for select patients with very early-stage iCCA, although this should be done on a protocol-only basis. Expert commentary: Appropriate preoperative patient selection and surgical technique are paramount to ensure optimal oncologic outcomes for patients with resectable iCCA. Improving systemic and locoregional therapy options may help decrease recurrence rates and improve long-term survival for this aggressive malignancy.

Treatment planning especially liver resection in cholangiocarcinoma (CCA) depends on the extension of tumor and lymph node metastasis which is included as a key criterion for operability. Magnetic resonance imaging (MRI) offers a rapid and powerful tool for the detection of lymph node metastasis (LNM) and in the current manuscript is assessed as a critical tool in the preoperative protocol for liver resection for treatment of CCA. However, the accuracy of MRI to detect LNM from CCA had yet to be comprehensively evaluated.

The accuracy of MRI to detect LNM was assessed in a cohort of individuals with CCA from the Cholangiocarcinoma Screening and Care Program (CASCAP), a screening program designed to reduce CCA in Northeastern Thailand by community-based ultrasound (US) for CCA. CCA-positive individuals are referred to one of the nine tertiary centers in the study to undergo a preoperative protocol that included enhanced imaging by MRI. Additionally, these individuals also underwent lymph node biopsies for histological confirmation of LNM (the "gold standard") to determine the accuracy of the MRI results.

MRI accurately detected the presence or absence of LNM in only 29 out of the 51 CCA cases (56.9%, 95% CI 42.2-70.7), resulting in a sensitivity of 57.1% (95% CI 34.0-78.2) and specificity of 56.7% (95% CI 37.4-74.5), with positive and negative predictive values of 48.0% (95% CI 27.8-68.7) and 65.4% (95% CI 44.3-82.8), respectively. The positive likelihood ratio was 1.32 (95% CI 0.76-2.29), and the negative likelihood ratio was 0.76 (95% CI 0.42-1.36).

MRI showed limited sensitivity and a poor positive predictive value for the diagnosis of LNM for CCA, which is of particular concern in this resource-limited setting, where simpler detection methods could be utilized that are more cost-effective in this region of Thailand. Therefore, the inclusion of MRI, a costly imaging method, should be reconsidered as part of protocol for treatment planning of CCA, given the number of false positives, especially as it is critical in determining the operability for CCA subjects.

The role of lymph node dissection (LND) in the treatment of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) remains controversial. We sought to systematically review all available evidence to determine the role of LND in patients with HCC and ICC. Studies that reported on LND, lymph node metastasis (LNM), and short- and long-term outcomes for patients with HCC or ICC survival were identified from PubMed, Cochrane, Embase, Scopus, and Web of Science databases. Data were extracted, synthesized, and analyzed using standard techniques. A total of 603 and 434 references were identified for HCC and ICC, respectively. Among HCC patients, the overall prevalence of LND was 51.6 % (95 % confidence interval (CI) 19.7-83.5) with an associated LNM incidence of 44.5 % (95 % CI 27.4-61.7). LNM was associated with a 3- and 5-year survival of 27.5 and 20.8 %, respectively. Among ICC patients, most patients 78.5 % (95 % CI 76.2-80.7) underwent LND; 45.2 % (95 % CI 39.2-51.2) had LNM. Three and 5-year survival among ICC patients with LNM was 0.2 % (95 % CI 0-0.7) and 0 %, respectively. While there are insufficient data to recommend a routine LND in all patients with HCC or ICC, the potential prognostic value of LND suggests that LND should at least be considered at the time of surgery.

Cholangiocarcinoma is a malignant neoplasm that originates from biliary epithelial cells. Complete tumor resection remains the most effective treatment of intra-hepatic or perihilar cholangiocarcinomas (PHCs). The objectives of this are to update and discuss methods that are likely to increase the resectability of cholangiocarcinomas, and to define the limits beyond which the risks of the treatments outweigh their benefits. We analyzed intra-hepatic cholangiocarcinomas and PHCs separately to determine the site of origin and the resectability of the tumor. We discussed the site at which to perform hepatic optimization prior to surgery, and whether liver transplantation might affect cholangiocarcinoma treatment.

The study investigates the expression and clinical role of GLP-1R in intrahepatic cholangiocarcinoma (ICC) tissues. ICC tissue, tissue around tumour and normal liver tissue samples from 176 ICC patients were investigated for GLP-1R expression by immunohistochemistry and western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. High GLP-1R expression levels were detected in tumor tissue samples. Kaplan-Meier method was used for survival analysis of patients follow-up data. Results showed that median survival time of patients with high GLP-1R positive expression in ICC tissue were 22 months. Median survival time of patients with low GLP-1R positive expression in ICC tissue were 19.8 months. There wasn't statistical difference (p = 0.332) between two groups. Immunohistochemistry semi-quantitative analysis showed that tissue differentiation is not prognostic risk factors. In patients with GLP-1R positive expression in ICC tissue, lymph node metastasis was important prognostic factors (p = 0.001). Although statistical analysis showed that GLP-1R can not be judged as a risk prognostic factors, GLP-1 might become a new target for therapy of ICC.