Figure - available from: International Journal of Hepatology
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Atypical small bile duct lesion. (a) Small interlobular bile duct shows cellular and nuclear atypia. HE. (b) Small interlobular bile duct shows nuclear atypia and disturbed polarity. HE.
Source publication
Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile...
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Background
Contrast-enhanced ultrasonography (CEUS) features of primary hepatobiliary neoplasms have been reported in dogs but no information is available in cats.
Methods
Qualitative and quantitative features of bile duct adenomas (BDAs, n=20), bile duct carcinomas (BDCs, n=16), and hepatocellular carcinomas (HCCs, n=8) are described in 44 cats....
Citations
... Recent data show that cellular senescence may be involved in the pathophysiology of CCAs [56,57]. Cell senescence is characterized by proliferative arrest, which is mediated by complex mechanisms, such as epigenetic modifications, genomic instability, DNA damage, chronic inflammation, and chromatin remodeling [58]. ...
Citation: Caligiuri, A.; Becatti, M.; Porro, N.; Borghi, S.; Marra, F.; Pastore, M.; Taddei, N.; Fiorillo, C.; Gentilini, A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants 2024, 13, 28. https://doi. Abstract: Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
... 18,45 Biliary hamartoma and biliary adenoma are regarded as possible precancerous lesions. 22,[53][54][55][56] Histological characteristics: The tumor cells are cuboidal or low columnar with scant cytoplasm, mostly moderately-highly differentiated and lack of mucus-secreting. However, mucus-secreting cells may be present in small duct type iCCA arising from septal bile duct. 2 Most tumor tissues are arranged into dense and regular small ductal structures (Fig. 4A, B). ...
Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
... Several oncogenic pathways have been investigated reflecting variability in progenitor cells, TME, epigenetic alterations, and carcinogen exposure [51][52][53]. All ICC subtypes arise from peribiliary gland (PBG) progenitor cells in the canals of Hering with the development of mucin-producing cholangiocytes [53,54]. Integrative genomic analysis of patients with ICC identified divergent inflammatory and proliferative classes of ICC based on gene expression profiles [55]. ...
Simple Summary
Primary liver tumors impose significant patient morbidity and mortality with overall poor prognosis. To date, conventional therapies have provided only modest survival benefit to patients. Developments in genomics, molecular biomarkers, and artificial intelligence are introducing novel patient-centered approaches to treat primary liver tumors to improve patient survival. Recent FDA-approved immune checkpoint inhibitors Atezolizumab–Bevacizumab and Durvalumab–Tremelimumab have demonstrated improved survival outcomes and in many cases disease downstaging to curative resection. Clinical trials investigating combined immunotherapy and locoregional therapy in advanced liver disease are ongoing with promising preliminary results. Future directions in liver cancer management will likely incorporate treatment algorithms based on individualized patient molecular biomarkers.
Abstract
Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers.
... The first one originates from large bile ducts with peribiliary glands (PBGs), whereas the second one originates from small ducts in connection with the Life 2022, 12, 2128 5 of 15 canals of Hering [35]. In both cases, iCC arises from hepatic stem/progenitor cells, located in the canals of Hering in the PBGs [36]. The histological classification divides iCC into adenocarcinoma with several degrees of differentiation. ...
Liver cancer represents a global health challenge with worldwide growth. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Indeed, approximately 90% of HCC cases have a low survival rate. Moreover, cholangiocarcinoma (CC) is another malignant solid tumor originating from cholangiocytes, the epithelial cells of the biliary system. It is the second-most common primary liver tumor, with an increasing course in morbidity and mortality. Tumor cells always show high metabolic levels, antioxidant modifications, and an increased iron uptake to maintain unlimited growth. In recent years, alterations in iron metabolism have been shown to play an important role in the pathogenesis of HCC. Several findings show that a diet rich in iron can enhance HCC risk. Hence, elevated iron concentration inside the cell may promote the development of HCC. Growing evidence sustains that activating ferroptosis may potentially block the proliferation of HCC cells. Even in CC, it has been shown that ferroptosis plays a crucial role in the treatment of tumors. Several data confirmed the inhibitory effect in cell growth of photodynamic therapy (PDT) that can induce reactive oxygen species (ROS) in CC, leading to an increase in malondialdehyde (MDA) and a decrease in intracellular glutathione (GSH). MDA and GSH depletion/modulation are crucial in inducing ferroptosis, suggesting that PDT may have the potential to induce this kind of cell death through these ways. A selective induction of programmed cell death in cancer cells is one of the main treatments for malignant tumors; thus, ferroptosis may represent a novel therapeutic strategy against HCC and CC.
... Likewise, experimental iCCA can be also derived from hepatocytes, particularly under the influence of Notch overexpression. [15][16][17][18] DDC-induced injury makes the oncogenically primed hepatocytes be reprogrammed to a cholangiocyte phenotype. 19,20 Both iCCA and extrahepatic cholangiocarcinoma exhibit higher incidence in non-Hispanic Asian/Pacific Islander populations than non-Hispanic White people. ...
Biliary tract cancer (BTC) that contains cholangiocarcinoma, gallbladder cancer, and ampullary cancer is highly malignant and mostly diagnosed in elderly patients. Over the past decades, human life has globally risen; thus, aging emerges as the primary risk factor for BTC. However, an effective treatment for this vulnerable population remains a large clinical challenge. As a result, the incidence and mortality of TBC remains high. Here, we discuss the potential link between aging and BTC from the aspects of molecular and cellular mechanisms, surgical resection, and chemotherapy. In addition, we update a number of clinical trials that are currently ongoing in elderly patients. The overview of BTC in elderly patients is expected to help develop a new therapeutic strategy tailored to this elderly population, ultimately improving their life quality. This is a review on the effects of aging on biliary tract cancer (BTC). We discuss the potential link between aging and BTC from the aspects of molecular mechanisms (including the DNA damage repair (DDR), cell senescence and the tumour microenvironment (TME)) and clinical challenges.
... BF is a rare disease that is usually misdiagnosed due to its nonspecific clinical symptoms and laboratory examination findings. Imaging [including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI)] usually reveal a multicystic tumor or complex mass with both solid and cystic components; these findings are very similar to cystadenoma or cystadenocarcinoma [2], intrahepatic cholangiocarcinoma [3], liver metastasis [4], and other lesions. However, the MRI findings have certain characteristics. ...
Background:
Biliary adenofibroma (BF) is a rare benign epithelial tumor with the possibility of malignant transformation. Its main pathological feature is a well-defined cystic or honeycomb mass. BF has no specific clinical manifestations or laboratory and imaging findings; thus, it is easily misdiagnosed before surgery. This report describes a case in which biliary cystadenoma was misdiagnosed preoperatively and BF was diagnosed postoperatively. The imaging features, particularly the magnetic resonance imaging (MRI) features, were analyzed and summarized.
Case summary:
A 68-year-old Chinese man was admitted to our hospital with a 2-mo history of abdominal discomfort. Following admission to our hospital, laboratory examinations showed normal tumor marker concentrations and liver function. Hepatocellular carcinoma was considered after contrast-enhanced ultrasound examination. MRI suggested the possibility of cystadenoma of the bile duct. However, postoperative pathological examination confirmed the diagnosis of BF. No local recurrence was found 1 mo after surgery.
Conclusion:
Our objective is to highlight the imaging diagnostic value of BF, especially on an MRI enhanced scan with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid.
... There is a large body of knowledge that VMC has more than a potential role as a preneoplastic lesion for CCA. This knowledge is based on several studies that have reported CCA arising from VMCs, suggesting malignant transformation from VMC to CCA, CCA having histologic similarities with VMC and DPM, and histologic similarity of CCA and VMC in K-ras and p53 mutated animal models inducing CCA (222)(223)(224)(225)(226)(227)(228)(229)(230)(231)(232). Most recently, the CCA with DPM pattern seems to have well-defined ARID1A genetic alterations (233). ...
ABSTRACT Liver cancer, predominantly hepatocellular carcinoma, is the second most common cause of cancer-related death in adults. Although infrequent in children, hepatocellular carcinoma is a terrifying diagnosis. Rising levels of obesity and obesity-associated lipid metabolic reprogramming of hepatocytes are increasing the prevalence of lipid-rich hepatocellular carcinoma in young adults. Most pediatric liver cancers occur in otherwise healthy liver, with some exceptions such as progressive familial intrahepatic cholestasis, hereditary tyrosinemia, alpha-1-antitrypsin deficiency, and genetic hemochromatosis. In the last decade, although aggressive multidisciplinary treatments including surgical resection and chemotherapy have remarkably improved patient outcomes in terms of decreased recurrence rate and increased overall survival rate, in children with unresectable liver cancer, the 5-year survival rate is still less than 20%. This chapter provides an overview of malignant epithelial tumors of the liver in children and adolescents. Hepatocellular carcinoma, lipid-rich hepatocellular carcinoma, fibrolamellar carcinoma, and cholangiocellular carcinoma are discussed.
... Despite rising incidence rates, ICC screening only targets specific populations that are at risk of developing this disease; screening indications include patients affected by trematodes such as Clonorchis sinensis (the most common cause of cholangiocarcinoma) and primary sclerosing cholangitis [5]. These risk factors, as well as others, promote malignant transformation of premalignant pathology such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct into ICC [6]. Unfortunately, ICC may develop idiopathically without any identifiable risk factors. ...
To this date, it is a major oncological challenge to optimally diagnose, stage, and manage intrahepatic cholangiocarcinoma (ICC). Imaging can not only diagnose and stage ICC, but it can also guide management. Hence, imaging is indispensable in the management of ICC. In this article, we review the pathology, epidemiology, genetics, clinical presentation, staging, pathology, radiology, and treatment of ICC.
... 8 Earlier diagnosis of precursor lesions of CCA can be beneficial for improving the prognosis of this highly malignant tumor. 9 There are several well-documented risk factors for ICCA such as PSC, parasitic diseases, and chemical agents. Other non-biliary chronic liver diseases and cirrhosis have long been identified as a significant risk factor in the development of hepatocellular carcinoma, but recently a similar pathogenesis has also been suggested for ICCA and its precursors. ...
... Other non-biliary chronic liver diseases and cirrhosis have long been identified as a significant risk factor in the development of hepatocellular carcinoma, but recently a similar pathogenesis has also been suggested for ICCA and its precursors. 9 Biliary intraepithelial neoplasia has been proven to be noninvasive precursor lesions of ICCA. Biliary intraepithelial neoplasia and its significance to biliary carcinogenesis have extensively been investigated in chronic biliary diseases, such as PSC, hepatolithiasis, or liver fluke infestations, because these are main known risk factors for the development of CCA, but much less investigation has been made about other major predisposing factors of ICCA, such as non-biliary cirrhosis secondary to chronic viral hepatitis, and NASH. ...
Background
Intrahepatic cholangiocarcinoma is a highly malignant tumor with a very short 5-year survival. Multistep carcinogenesis has been suggested as the main pathway for the development of this tumor. Main suggested precursors have been (1) biliary intraepithelial neoplasia (BilIN) and (2) intraductal papillary neoplasm of bile duct (IPNB). The former is flat and does not produce grossly and radiologically detectable mass lesion, but the latter produces grossly identifiable lesion.
Objectives
The development of bile duct dysplasia (BilIN) in chronic biliary diseases has been investigated and proved, but the incidence of BilIN in non-biliary causes of cirrhosis such as hepatitis B and non-alcoholic steatohepatitis has very rarely been investigated. In this study, we have tried to find out the prevalence of BilIN in non-biliary cirrhosis.
Patients and Methods
During the study period (2017-2018) in 100 explanted livers with the diagnosis of non-biliary cirrhosis, thorough sampling (at least 20 sections) was performed, and pathologic sections were studied for the presence of BilIN.
Results
In the 100 studied livers with different diagnoses of non-biliary causes of cirrhosis, 31% of cases showed BilIN-1 and 2% of cases showed BiliIN-2. No case of BilIN-3 has been identified.
Discussion and Conclusions
Non-biliary causes of cirrhosis should be considered as precursors of cholangiocarcinoma (BilIN); however, the incidence of this occurrence is low.
... Auch in der Entstehung von Cholangiokarzinomen wird eine mehrstufige Tumorentwicklung beschrieben. Als prämaligne Läsionen mit unterschiedlichem Malignitätsrisiko finden sich intraduktale papilläre Neoplasien der Gallengänge (IPNB) und biliäre intraepitheliale Neoplasien (BilIN; [19]). Biliäre intraepitheliale Neoplasien sind aufgrund ihres flachen Wachstums mittels Bildgebung nicht abgrenzbar und werden im Rahmen der histologischen Aufarbeitung von resezierten CCC oder Gallenblasen entdeckt. ...
Clinical/methodical issue
Bile duct diseases can be found in all age groups and show an increased prevalence in northern Europe. Pathologies range from benign diseases to malignant tumors with very poor survival.
Standard radiological methods
Magnetic resonance imaging (MRI) and computed tomography (CT) are the radiological methods of choice for a detailed evaluation of the bile duct system in addition to sonography. By assessing the lumen and the wall of the bile ducts as well as the surrounding structures, both obstructive and nonobstructive pathologies can be diagnosed and differentiated with high sensitivity and specificity.
Methodical innovations
Technical developments with postprocessing modalities as well as the use of biliary-excreted liver-specific MR contrast agents improve the diagnosis of bile duct diseases and enable morphological and functional assessment.
Performance
Due to high patient tolerance, minimal procedural risk in contrast to invasive endoscopic methods and the possibility of three-dimensional post-processing, beside CT, MRI with magnetic resonance cholangiography (MRC) represents the method of choice in patients with sonographically or clinically suspected bile duct disease and has significantly reduced the indications of diagnostic endoscopic retrograde cholangiopancreatography (ERCP). A complementary multimodality and multiparametric imaging approach is particularly helpful for preoperative assessment.
Practical recommendations
Rapidly evolving technology for both MRI and CT represent opportunities and challenges. By understanding the advantages and limitations of modern MR and CT techniques and by knowing the spectrum of bile duct pathologies, improved diagnosis and narrowing of possible differential diagnosis can be achieved.
