Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.
- MeSH
- cholangiokarcinom * patologie etiologie genetika MeSH
- idiopatické střevní záněty * komplikace patologie MeSH
- kolorektální nádory * patologie etiologie genetika MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory žlučových cest * patologie etiologie genetika MeSH
- sklerozující cholangitida * komplikace patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Biliary drainage is then one of the necessary procedures to help patients suffering from icterus to reduce serum bilirubin levels and relieve symptoms. The aim of this study was identifying risk factors for survival in patients with cholangiocarcinoma (CCA) treated with percutaneous transhepatic biliary drainage (PTBD) and to develop a simple scoring system predicting survival from PTBD insertion. This single-centre retrospective study included 175 consecutive patients undergoing PTBD for extrahepatic CCA (perihilar and distal). Prognostic factors affecting survival of patients with CCA treated with PTBD were analysed. A multivariate analysis showed that mass forming tumor with mass larger than 5 cm and presence of metastasis at the time of PTBD served as a negative prognostic factor (p = 0.002), better survival was associated with lower preprocedural bilirubin and lower CRP (p = 0.003). Multivariate analysis identified two significant risk factors for 3-month mortality: mass-forming tumors and bilirubin levels exceeding 185 μmol/L. A simple scoring system was developed to predict 3-month mortality after PTBD in patients with advanced CCA, demonstrating 86.3% negative predictive value and 43.2% positive predictive value.
- MeSH
- bilirubin krev MeSH
- cholangiokarcinom * mortalita terapie patologie MeSH
- dospělí MeSH
- drenáž * metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory žlučových cest * mortalita terapie patologie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The gut microbiota, composed by several species of microorganisms, works to preserve the liver-gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery. METHODS: A literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development. RESULTS: Bacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA's biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment. CONCLUSION: The correct use of nutrition for microbiota modulation according to each patient's needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.
Cholangiocelulární karcinom je relativně vzácný maligní nádor vycházející z biliárních epitelií, který může vznikat v intra- i extrahepatálních žlučovodech, ve žlučníku a ve Vaterské ampule. Tento přehledový článek se věnuje problematice cholangiocelulárního karcinomu z pohledu histopatologa. Kromě shrnutí základních morfologických, imunohistochemických a molekulárně genetických charakteristik jednotlivých typů cholangiokarcinomu a prekancerózních lézí se zaměřuje na problematiku peroperačních biopsií a na změny v aktuálním 8. vydání TNM klasifikace. Součástí sdělení je makroskopická i mikroskopická obrazová dokumentace z naší praxe a přehled recentní literatury.
Cholangiocarcinoma is a relatively rare malignant tumor arising from the biliary epithelium of the intra- and extrahepatic bile ducts, the gallbladder, and the ampulla of Vater. This review article presents cholangiocarcinoma from the routine histopathological point of view. In addition to an overview of basic morphological, immunohistochemical, and molecular genetic characteristics of cholangiocarcinoma subtypes and precancerous lesions, the article is focused on intraoperative biopsies and on changes in the 8th edition of the TNM classification. Macroscopic and microscopic photo documentation and a review of recent literature are included.
- MeSH
- cholangiokarcinom patologie MeSH
- lidé MeSH
- nádory žlučových cest * chirurgie patologie MeSH
- žlučové cesty extrahepatické patologie MeSH
- žlučové cesty intrahepatální patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: The aim of the study was to calculate the short-term and long-term outcomes of curative-intent surgery in distal cholangiocarcinoma (DCC) patients to identify potential prognostic factors. PATIENTS AND METHODS: A retrospective cohort study of 32 consecutive DCC patients treated with pancreaticoduodenectomy between 2009-2017. The clinicopathological and histopathological data were evaluated for prognostic factors using the univariable Cox regression analysis. The Overall Survival (OS) was estimated using the Kaplan-Meier analysis. RESULTS: The study comprised a total of 32 patients, with a mean age of 65.8 (± 9.0) years at the time of surgery. R0 resection was achieved in 25 (86.2%) patients, 19 (65.5%) patients received adjuvant oncological therapy. The OS rates at 1, 3 and 5 years were 62.5%, 37.5% and 21.9%, respectively. The 90-day mortality was 3/32 (9.4%) accounting for one-fourth of the first-year mortality rate. The median OS was 28.5 months. The only statistically significant prognostic factor was vascular resection, which was associated with worse OS in the univariable analysis (HR: 3.644; 95%-CI: 1.179-11.216, P=0.025). An age less than 65 years, ASA grade I/II, hospital stay of fewer than 15 days, R0 resection, lymph node ratio less than 0.2 and adjuvant oncological therapy tended to be associated with better OS but without statistically significant relevance. CONCLUSION: The main factor directly influencing the survival of DCC patients is surgical complications. Surgical mortality comprises a significant group of patients, who die in the first year following pancreaticoduodenectomy. Vascular resection is the most important negative prognostic factor for long-term survival.
- MeSH
- cholangiokarcinom * chirurgie patologie MeSH
- lidé MeSH
- nádory žlučových cest * chirurgie patologie MeSH
- pankreatoduodenektomie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři MeSH
- výsledek terapie MeSH
- žlučové cesty intrahepatální patologie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
Správná indikace je jedním z klíčových předpokladů úspěchu transplantační léčby a je též významným regulátorem řešení nepoměru mezi potřebou transplantace a reálnou kapacitou transplantačního programu. Pro zařazení na čekací listinu je rozhodujícím faktorem pravděpodobnost dosažení benefitu, který může transplantace jater průměrnému kandidátovi poskytnout. Velikost minimálního akceptovatelného benefitu je dána především dynamikou čekací listiny, většina programů pracuje s 50% pravděpodobností 5letého přežití po transplantaci. Transplantace jater je nadále výkonem určeným k radikální léčbě smrtelných jaterních chorob jiným způsobem neléčitelných s cílem dosažení dlouhodobého přežití. K současným posunům v indikacích přispívá růst incidence hepatocelulárního karcinomu a nealkoholové tukové choroby jater. Zlepšení intenzivní péče pak otvírá možnost indikovat k transplantaci pacienty s akutním selháním jater nasedajícím na selhání chronické (acute-on-chronic liver failure – ACLF). Zlepšení chirurgické a onkologické péče pak vede k indikaci transplantace u pacientů s hepatocelulárním karcinomem, který se velikostí nachází již za hranicemi standardních kritérií. A znovu se otevírá i téma transplantací nemocným s cholangiocelulárním karcinomem a metastázami kolorektálního karcinomu. Tyto indikace jsou vnímány kontroverzně a dochází ke značným regionálním variacím v praktickém přístupu. Nově je diskutována definice marné transplantace a kritérií odmítnutí transplantační léčby.
To achieve satisfactory results of liver transplantation, proper selection of transplant candidates is essential. Moreover, indication process is crucial regulator to solve disparity between need for transplantation and capacity of transplant services. Any patient entering the transplant waiting list must have a chance to achieve at least average transplant benefit, currently described as 50% chance to survive 5 years after liver replacement. Until now, liver transplantation is procedure designed to treat life threatening liver disorders with aim to offer long-term survival. Nevertheless, an increase in incidence of hepatocellular carcinoma, and nonalcoholic fatty liver disease caused changes in indication spectrum. Improvement in intensive care turned interest to patients with acute-on-chronic liver failure even caused by acute alcoholic hepatitis. Advances in surgery and oncology broadened indications of patients with hepatocellular carcinoma behind standard criteria, and reopened interest in field of cholangiocellular cancer and even liver metastases of colorectal cancer. These criteria are still under development, and full of controversies and broad local variation in clinical practice is present. Entity of futile transplantation is discussed recently with aim to define generally acceptable criteria to deny transplant treatment in too risky patients.
- MeSH
- akutní selhání jater patologie terapie MeSH
- alkoholická hepatitida patologie terapie MeSH
- cholangiokarcinom patologie terapie MeSH
- hepatocelulární karcinom patologie terapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nealkoholová steatóza jater komplikace patologie terapie MeSH
- přežití tkáně MeSH
- transplantace jater * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cholangiocelulární karcinom (CCC) je prognosticky nepříznivým zhoubným nádorem jater, jaterních i mimojaterních žlučovodů a žlučníku. Článek představuje shrnutí problematiky CCC z pohledu patologa; kromě klasického popisu makroskopické a mikroskopické morfologie se věnuje rozdělení CCC na intrahepatální (periferní) a hilový či extrahepatální subtyp, přičemž tyto typy nádorů mají odlišné morfologické a molekulární vlastnosti i rozdílnou prognózu, mj. s ohledem na rozdílné možnosti chirurgického odstranění. Hilový a extrahepatální CCC pak sdílejí biologické vlastnosti s duktálním adenokarcinomem pankreatu. Článek dále obsahuje přehled různých typů prekancerózních lézí žlučových cest, představuje novinky v 8. vydání klasifikace TNM týkající se nádorů žlučových cest a shrnuje problematiku praxe histopatologické diagnostiky CCC včetně přehledu imunohistochemických metod a tématu peroperační histologické diagnosticky CCC ve zmraženém řezu.
Cholangiocellular carcinoma (CCC) is a malignant tumor harboring a poor prognosis, occurring in the liver, gallbladder and in extra- or intrahepatic biliary ducts. The article reviews the topic concerning CCC from the point of view of a surgical pathologist. The paper deals with classification of CCC into an intrahepatic/peripheral and hilar/extrahepatic subtype with different morphology, molecular features and prognosis; together with classical gross pathology, histopathology and natural history of CCC. Hilar and extrahepatic CCC share some biological characteristics with pancreatic ductal adenocarcinoma. The review comprises various types of precancerous lesions of biliary tract, summarizes updates in 8th edition of TNM classification and describes the routine issues concerning histopathological diagnostics of CCC, including immunohistochemistry and frozen section methods.
- MeSH
- biopsie MeSH
- cholangiokarcinom * diagnóza klasifikace patologie MeSH
- diferenciální diagnóza MeSH
- imunohistochemie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- prekancerózy klasifikace MeSH
- žlučník patologie MeSH
- žlučové cesty anatomie a histologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- buněčné jádro účinky léků MeSH
- cholangiokarcinom farmakoterapie genetika patologie MeSH
- cytoplazma účinky léků MeSH
- dasatinib aplikace a dávkování MeSH
- fosfoproteiny genetika MeSH
- fosforylace účinky léků MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protein-serin-threoninkinasy genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- signální transdukce účinky léků MeSH
- skupina kinas odvozených od src-genu antagonisté a inhibitory genetika MeSH
- tyrosin genetika MeSH
- tyrosinkinasa p56(lck), specifická pro lymfocyty genetika MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
BACKGROUND & AIMS: Myeloid cell leukemia 1 (MCL1), a prosurvival member of the BCL2 protein family, has a pivotal role in human cholangiocarcinoma (CCA) cell survival. We previously reported that fibroblast growth factor receptor (FGFR) signalling mediates MCL1-dependent survival of CCA cells in vitro and in vivo. However, the mode and mechanisms of cell death in this model were not delineated. METHODS: Human CCA cell lines were treated with the pan-FGFR inhibitor LY2874455 and the mode of cell death examined by several complementary assays. Mitochondrial oxidative metabolism was examined using a XF24 extracellular flux analyser. The efficiency of FGFR inhibition in patient-derived xenografts (PDX) was also assessed. RESULTS: CCA cells expressed two species of MCL1, a full-length form localised to the outer mitochondrial membrane, and an N terminus-truncated species compartmentalised within the mitochondrial matrix. The pan-FGFR inhibitor LY2874455 induced non-apoptotic cell death in the CCA cell lines associated with cellular depletion of both MCL1 species. The cell death was accompanied by failure of mitochondrial oxidative metabolism and was most consistent with necrosis. Enforced expression of N terminus-truncated MCL1 targeted to the mitochondrial matrix, but not full-length MCL1 targeted to the outer mitochondrial membrane, rescued cell death and mitochondrial function. LY2874455 treatment of PDX-bearing mice was associated with tumour cell loss of MCL1 and cell necrosis. CONCLUSIONS: FGFR inhibition induces loss of matrix MCL1, resulting in cell necrosis. These observations support a heretofore unidentified, alternative MCL1 survival function, namely prevention of cell necrosis, and have implications for treatment of human CCA. LAY SUMMARY: Herein, we report that therapeutic inhibition of a cell receptor expressed by bile duct cancer cells resulted in the loss of a critical survival protein termed MCL1. Cellular depletion of MCL1 resulted in the death of the cancer cells by a process characterised by cell rupture. Cell death by this process can stimulate the immune system and has implications for combination therapy using receptor inhibition with immunotherapy.
- MeSH
- buněčná smrt účinky léků MeSH
- cholangiokarcinom farmakoterapie metabolismus patologie MeSH
- indazoly farmakologie MeSH
- indoly farmakologie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory žlučových cest farmakoterapie metabolismus patologie MeSH
- nekróza MeSH
- oxidace-redukce MeSH
- protein MCL-1 antagonisté a inhibitory metabolismus MeSH
- receptory fibroblastových růstových faktorů antagonisté a inhibitory MeSH
- sulfonamidy farmakologie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- cholangiokarcinom * diagnóza chirurgie patologie MeSH
- imunohistochemie veterinární MeSH
- keratiny izolace a purifikace MeSH
- laparotomie metody veterinární MeSH
- nádory podle histologického typu MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- kazuistiky MeSH
