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1.
Am J Surg Pathol ; 48(6): 751-760, 2024 Jun 01.
Article de Anglais | MEDLINE | ID: mdl-38584480

RÉSUMÉ

Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers.


Sujet(s)
Tumeurs des canaux biliaires , Marqueurs biologiques tumoraux , Protéines de liaison au calcium , Cholangiocarcinome , Immunohistochimie , Ostéopontine , Humains , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/classification , Cholangiocarcinome/mortalité , Cholangiocarcinome/composition chimique , Cholangiocarcinome/diagnostic , Ostéopontine/analyse , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/classification , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/diagnostic , Mâle , Femelle , Adulte d'âge moyen , Marqueurs biologiques tumoraux/analyse , Sujet âgé , Études rétrospectives , Protéines de liaison au calcium/analyse , Adulte , Sujet âgé de 80 ans ou plus , Protéines tumorales/analyse , Valeur prédictive des tests , Conduits biliaires intrahépatiques/anatomopathologie , Conduits biliaires intrahépatiques/composition chimique
2.
Biochim Biophys Acta Gen Subj ; 1864(12): 129708, 2020 12.
Article de Anglais | MEDLINE | ID: mdl-32810561

RÉSUMÉ

BACKGROUND: Ursolic acid (UA) is a natural triterpenoid which possesses anti-cancer activity. However, little is known regarding the activity and molecular mechanism of UA in cholangiocarcinoma (CCA). Thus, we investigated the effects of UA on growth inhibition and apoptosis induction through biomolecular changes in KKU-213 and KKU-055 CCA cell lines. METHODS: The anti-proliferative effect of UA against CCA cells was evaluated using SRB assay. Changes in biomolecules were assessed by SR-FTIR microspectroscopy combined with PCA and conventional methods (i.e., Annexin V-FITC/PI staining for lipid alteration and apoptosis induction; Western blot analysis and caspase-3/7 activity assay for apoptotic protein detection). RESULTS: UA suppressed the proliferation of CCA cells in a dose- and time-dependent manner. SR-FTIR data revealed a significant alteration in lipids attributable to changes in apoptotic cell membranes, confirmed by Annexin V-FITC/PI staining. SR-FTIR data showed that UA promoted changes in the protein secondary structure. Elevated expression of Bax and decreased expression of Bcl-2 and survivin/BIRC5 along with augmented caspase-3/7 activity supported alterations in apoptosis-related proteins. CONCLUSIONS: SR-FTIR microspectroscopy was successfully used as a label-free technique to monitor apoptosis-induced biomolecular changes in UA-treated CCA cells. UA exerted the cytotoxic and apoptotic activities in CCA cells through alterations in membrane lipids and apoptotic proteins. UA could be a potential anti-CCA candidate and a chemical starting point for the discovery of novel anti-cancer agents. SIGNIFICANCE: Our present study showed the first evidence that UA exhibited the anti-proliferative and pro-apoptotic activities toward CCA cells through changes in biomolecules, notably lipids and proteins.


Sujet(s)
Antinéoplasiques d'origine végétale/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Tumeurs des canaux biliaires/traitement médicamenteux , Cholangiocarcinome/traitement médicamenteux , Triterpènes/pharmacologie , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/anatomopathologie , Lignée cellulaire tumorale , Cholangiocarcinome/composition chimique , Cholangiocarcinome/anatomopathologie , Humains , Spectroscopie infrarouge à transformée de Fourier/instrumentation , Synchrotrons/instrumentation ,
3.
Hum Pathol ; 96: 48-55, 2020 02.
Article de Anglais | MEDLINE | ID: mdl-31931021

RÉSUMÉ

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma showing variable degrees of differentiation toward hepatocellular and cholangiocellular carcinoma. Its great heterogeneity in term of morphology, immunophenotype, molecular, radiological and clinical features represents a challenge still to overcome. The multidisciplinary 2018 International Consensus on the nomenclature of cHCC-CCA allowed to define key issues of this entity. Here we review the historical controversies of cHCC-CCA, resume the key elements of the 2018 consensus, now incorporated in the 2019 WHO classification, and propose a short survival guide to help surgical pathologists facing cHCC-CCA in their routine workup.


Sujet(s)
Carcinome hépatocellulaire/anatomopathologie , Cholangiocarcinome/anatomopathologie , Tumeurs du foie/anatomopathologie , Tumeurs complexes et mixtes/anatomopathologie , Marqueurs biologiques tumoraux/analyse , Marqueurs biologiques tumoraux/génétique , Biopsie , Carcinome hépatocellulaire/composition chimique , Carcinome hépatocellulaire/génétique , Carcinome hépatocellulaire/thérapie , Cholangiocarcinome/composition chimique , Cholangiocarcinome/génétique , Cholangiocarcinome/thérapie , Humains , Immunohistochimie , Tumeurs du foie/composition chimique , Tumeurs du foie/génétique , Tumeurs du foie/thérapie , Techniques de diagnostic moléculaire , Tumeurs complexes et mixtes/composition chimique , Tumeurs complexes et mixtes/génétique , Tumeurs complexes et mixtes/thérapie , Valeur prédictive des tests , Pronostic
4.
Pathol Res Pract ; 215(12): 152685, 2019 Dec.
Article de Anglais | MEDLINE | ID: mdl-31727501

RÉSUMÉ

BACKGROUND: The pancreatobiliary carcinomas are characterized by presence of desmoplastic stroma. Overexpression of secreted protein acid and rich in cysteine (SPARC), a matrix producing agent has been documented in pancreatic ductal adenocarcinomas, with survival benefits. This study was targeted to see if SPARC expression in pancreatobiliary carcinomas is responsible for stromal desmoplasia and its prognostic significance. METHODS: In this retrospective study 48 cases of pancreatic cancer and 27 cases of cholangiocarcinoma were analyzed. The expression pattern of SPARC and vascular endothelial growth factor (VEGF) (angiogenic factors) was evaluated by immunohistochemistry on formalin fixed paraffin embedded tissues. Immunoreactivity was scored semi quantitatively based on stain intensity and stain distribution. SPARC expression was correlated with tumor histology, stromal desmoplasia, VEGF expression, various histological parameters and overall survival in patients. Real time polymerase chain reaction was performed in few cases to validate the immunohistochemistry expression pattern. RESULTS: SPARC expression was high in peritumoral stroma in pancreatic carcinoma than in pancreatic controls; however, SPARC expression pattern was not grossly different in desmoplastic and non-desmoplastic pancreatobiliary carcinomas and in cholangiocarcinomas. No definite correlation was noted between SPARC expression and histological markers of severity and overall survival data. CONCLUSIONS: The relevance of SPARC expression in pancreato-biliary carcinomas though may still be important for therapeutic decision making, it is not responsible for peritumoral stromal desmoplasia in these tumors and it does not have any significant prognostic implication.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Carcinome du canal pancréatique/composition chimique , Cholangiocarcinome/composition chimique , Ostéonectine/analyse , Tumeurs du pancréas/composition chimique , Cellules stromales/composition chimique , Adulte , Sujet âgé , Tumeurs des canaux biliaires/génétique , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/anatomopathologie , Carcinome du canal pancréatique/génétique , Carcinome du canal pancréatique/mortalité , Carcinome du canal pancréatique/anatomopathologie , Prolifération cellulaire , Cholangiocarcinome/génétique , Cholangiocarcinome/mortalité , Cholangiocarcinome/anatomopathologie , Études transversales , Femelle , Fibrose , Humains , Mâle , Adulte d'âge moyen , Ostéonectine/génétique , Tumeurs du pancréas/génétique , Tumeurs du pancréas/mortalité , Tumeurs du pancréas/anatomopathologie , Études rétrospectives , Cellules stromales/anatomopathologie , Facteur de croissance endothéliale vasculaire de type A/analyse
5.
Cancer Cell ; 35(6): 932-947.e8, 2019 06 10.
Article de Anglais | MEDLINE | ID: mdl-31130341

RÉSUMÉ

We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.


Sujet(s)
Tumeurs des canaux biliaires/génétique , Marqueurs biologiques tumoraux/génétique , Carcinome hépatocellulaire/génétique , Cholangiocarcinome/génétique , Analyse de profil d'expression de gènes , Tumeurs du foie/génétique , Tumeurs complexes et mixtes/génétique , Nestine/génétique , Transcriptome , Asie , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/classification , Tumeurs des canaux biliaires/anatomopathologie , Marqueurs biologiques tumoraux/analyse , Carcinome hépatocellulaire/composition chimique , Carcinome hépatocellulaire/classification , Carcinome hépatocellulaire/anatomopathologie , Cholangiocarcinome/composition chimique , Cholangiocarcinome/classification , Cholangiocarcinome/anatomopathologie , Bases de données génétiques , Femelle , Régulation de l'expression des gènes tumoraux , Réseaux de régulation génique , Humains , Immunohistochimie , Tumeurs du foie/composition chimique , Tumeurs du foie/classification , Tumeurs du foie/anatomopathologie , Mâle , Tumeurs complexes et mixtes/composition chimique , Tumeurs complexes et mixtes/classification , Tumeurs complexes et mixtes/anatomopathologie , Nestine/analyse , Valeur prédictive des tests , Pronostic , Régulation positive
6.
Cancer Immunol Immunother ; 68(3): 467-478, 2019 Mar.
Article de Anglais | MEDLINE | ID: mdl-30607549

RÉSUMÉ

BACKGROUND: The tumor-expressed CD73 ectonucleotidase generates immune tolerance and promotes invasiveness via adenosine production from degradation of AMP. While anti-CD73 blockade treatment is a promising tool in cancer immunotherapy, a characterization of CD73 expression in human hepatobiliopancreatic system is lacking. PATIENTS AND METHODS: CD73 expression was investigated by immunohistochemistry in a variety of non-neoplastic and neoplastic conditions of the liver, pancreas, and biliary tract. RESULTS: CD73 was expressed in normal hepatobiliopancreatic tissues with subcellular-specific patterns of staining: canalicular in hepatocytes, and apical in cholangiocytes and pancreatic ducts. CD73 was present in all hepatocellular carcinoma (HCC), in all pancreatic ductal adenocarcinoma (PDAC), and in the majority of intra and extrahepatic cholangiocellular carcinomas, whereas it was detected only in a subset of pancreatic neuroendocrine neoplasms and almost absent in acinar cell carcinoma. In addition to the canonical pattern of staining, an aberrant membranous and/or cytoplasmic expression was observed in invasive lesions, especially in HCC and PDAC. These two entities were also characterized by a higher extent and intensity of staining as compared to other hepatobiliopancreatic neoplasms. In PDAC, aberrant CD73 expression was inversely correlated with differentiation (p < 0.01) and was helpful to identify isolated discohesive tumor cells. In addition, increased CD73 expression was associated with reduced overall survival (HR 1.013) and loss of E-Cadherin. CONCLUSIONS: Consistent CD73 expression supports the rationale for testing anti-CD73 therapies in patients with hepatobiliopancreatic malignancies. Specific patterns of expression could also be of help in the routine diagnostic workup.


Sujet(s)
5'-Nucleotidase/analyse , Tumeurs des canaux biliaires/composition chimique , Voies biliaires/composition chimique , Tumeurs du foie/composition chimique , Foie/composition chimique , Pancréas/composition chimique , Tumeurs du pancréas/composition chimique , 5'-Nucleotidase/antagonistes et inhibiteurs , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/anatomopathologie , Carcinome hépatocellulaire/composition chimique , Carcinome hépatocellulaire/mortalité , Carcinome hépatocellulaire/anatomopathologie , Carcinome du canal pancréatique/composition chimique , Carcinome du canal pancréatique/mortalité , Carcinome du canal pancréatique/anatomopathologie , Cholangiocarcinome/composition chimique , Cholangiocarcinome/mortalité , Cholangiocarcinome/anatomopathologie , Transition épithélio-mésenchymateuse , Protéines liées au GPI/analyse , Protéines liées au GPI/antagonistes et inhibiteurs , Humains , Immunohistochimie , Tumeurs du foie/mortalité , Tumeurs du foie/anatomopathologie , Tumeurs du pancréas/mortalité , Tumeurs du pancréas/anatomopathologie , Pronostic
7.
Virchows Arch ; 474(1): 29-37, 2019 Jan.
Article de Anglais | MEDLINE | ID: mdl-30377796

RÉSUMÉ

Intrahepatic cholangiocarcinoma (ICC) has universally poor outcome, mainly due to its late clinical presentation. Identification of specific biomarkers and development of effective treatment are still urgently required. Mutations in PBRM-1 and BAP-1 genes, and the expression of S100P have been related to survival in ICC. miR-31 seems also to play important regulatory functions in ICC and it directly regulates BAP-1 expression in lung cancer. In this study, tissue expression of BAP-1, PBRM-1, S100P, and miR-31 was investigated in ICC and correlated with clinical-pathological features. Sixty-one consecutive patients who underwent curative hepatic resection for ICC were enrolled. None received any therapy prior to surgery. Immunostaining for BAP-1, PBRM-1, and S100P, and in situ hybridization for miR-31 were performed, using tissue microarray slides. A strong retained expression of BAP-1 and PBRM-1 was associated with a reduced overall (p = 0.04 and p = 0.002, respectively) and disease-free survival (p = 0.05 and p = 0.02, respectively). An overexpression of S100P was related to a reduced overall survival (p = 0.005). The multivariate analyses identified the presence of perineural invasion and the retained PBRM-1 expression as independent predictors of worse overall [p = 0.02, hazard ratio (HR) = 2.25 (1.16-4.39) and p = 0.001, HR = 3.13 (1.56-6.28), respectively] and disease-free survivals [p = 0.03, HR = 2.43 (1.09-5.4) and p = 0.03, HR = 2.51 (1.11-5.67), respectively]. An overexpression of S100P was predictive of a worse overall survival [p = 0.02, HR = 1.66 (1.08-2.55)]. High levels of miR-31 were significantly associated to a low expression of BAP-1 protein (p = 0.03). In ICC, a retained expression of BAP-1 and PBRM-1, and an overexpression of S100P are related to a poor prognosis.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Cholangiocarcinome/composition chimique , Protéines nucléaires/analyse , Facteurs de transcription/analyse , Protéines suppresseurs de tumeurs/analyse , Ubiquitin thiolesterase/analyse , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/génétique , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/chirurgie , Marqueurs biologiques tumoraux/génétique , Protéines de liaison au calcium/analyse , Cholangiocarcinome/génétique , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/chirurgie , Protéines de liaison à l'ADN , Évolution de la maladie , Survie sans rechute , Femelle , Hépatectomie/méthodes , Humains , Immunohistochimie , Hybridation in situ , Laparoscopie , Mâle , microARN/génétique , Adulte d'âge moyen , Protéines tumorales/analyse , Études rétrospectives , Facteurs temps , Analyse sur puce à tissus , Résultat thérapeutique
8.
Virchows Arch ; 474(1): 39-46, 2019 Jan.
Article de Anglais | MEDLINE | ID: mdl-30349952

RÉSUMÉ

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Cholangiocarcinome/composition chimique , Protéine du locus du complexe MDS1 et EVI1/analyse , Sujet âgé , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/thérapie , Cholangiocarcinome/mortalité , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/thérapie , Évolution de la maladie , Femelle , Hépatectomie , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Survie sans progression , Facteurs temps , Résultat thérapeutique
9.
Anticancer Res ; 38(9): 5547-5550, 2018 Sep.
Article de Anglais | MEDLINE | ID: mdl-30194215

RÉSUMÉ

Concurrent laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma is rare and no prior report has been found through a PubMed search. Here we report such a case of a 51-year old obese male presenting with hoarseness and trouble swallowing for 2 to 3 months. Imaging findings of computer tomography (CT) and magnetic resonance imaging (MRI) with and without contrast were suspicious for a T3N2 supraglottic laryngeal cancer. Laryngeal biopsy showed a well differentiated squamous cell carcinoma (SCC). As part of the evaluation of the laryngeal SCC, MRI abdomen showed an enhancing mass (4.6 cm in the greatest dimension) with diffusion restriction and capsular retraction in the right lobe of the liver. Ultrasound-guided percutaneous biopsy of the liver revealed a moderately differentiated adenocarcinoma, that was strongly and diffusely positive for CK7 and CK19, weakly positive for CDX2, and negative for HepPar 1, glypican 3, CK20, PSA and TTF1. The immunohistochemistry profile was consistent with cholangiocarcinoma. This is a unique case of laryngeal squamous cell carcinoma with concurrent cholangiocarcinoma. The prognosis was poor and the patient was placed in hospice care in two months after the diagnoses. To the best of our knowledge, this is the first documented case of synchronous laryngeal squamous cell carcinoma and intrahepatic cholangiocarcinoma. The pathogenesis, diagnosis and treatment of the diseases are discussed.


Sujet(s)
Tumeurs des canaux biliaires/anatomopathologie , Carcinome épidermoïde/anatomopathologie , Cholangiocarcinome/anatomopathologie , Tumeurs de la tête et du cou/anatomopathologie , Tumeurs du larynx/anatomopathologie , Tumeurs primitives multiples/anatomopathologie , Obésité/complications , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/imagerie diagnostique , Marqueurs biologiques tumoraux/analyse , Biopsie , Carcinome épidermoïde/composition chimique , Carcinome épidermoïde/imagerie diagnostique , Cholangiocarcinome/composition chimique , Cholangiocarcinome/imagerie diagnostique , Troubles de la déglutition/étiologie , Évolution de la maladie , Issue fatale , Tumeurs de la tête et du cou/composition chimique , Tumeurs de la tête et du cou/imagerie diagnostique , Enrouement/étiologie , Humains , Immunohistochimie , Tumeurs du larynx/composition chimique , Tumeurs du larynx/imagerie diagnostique , Imagerie par résonance magnétique , Mâle , Adulte d'âge moyen , Tumeurs primitives multiples/composition chimique , Tumeurs primitives multiples/imagerie diagnostique , Obésité/diagnostic , Carcinome épidermoïde de la tête et du cou , Tomodensitométrie
11.
Hum Pathol ; 76: 100-109, 2018 06.
Article de Anglais | MEDLINE | ID: mdl-29514108

RÉSUMÉ

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy.


Sujet(s)
Tumeurs des canaux biliaires/génétique , Marqueurs biologiques tumoraux/génétique , Cholangiocarcinome/génétique , Amplification de gène , Récepteur FGFR2/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/virologie , Marqueurs biologiques tumoraux/analyse , Chine , Cholangiocarcinome/composition chimique , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/virologie , Femelle , Prédisposition génétique à une maladie , Virus de l'hépatite B/isolement et purification , Humains , Immunohistochimie , Hybridation fluorescente in situ , Mâle , Adulte d'âge moyen , Stadification tumorale , Phénotype , Pronostic , Récepteur FGFR2/analyse , Translocation génétique
12.
Liver Int ; 38(1): 113-124, 2018 01.
Article de Anglais | MEDLINE | ID: mdl-28608943

RÉSUMÉ

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome-wide molecular features and clinical significance remain unclear. METHODS: Based on CD status, we stratified iCCAs into iCCA with CD (n=20) and iCCA without CD (n=102), and performed an integrative analysis using transcriptomic and clinicopathological profiles. RESULTS: iCCA with CD revealed less aggressive histopathological features compared to iCCA without CD, and iCCA with CD showed favourable clinical outcomes of overall survival and time to recurrence than iCCA without CD (P<.05 for all). Transcriptomic profiling revealed that iCCA with CD resembled an inflammation-related subtype, while iCCA without CD resembled a proliferation subtype. In addition, we identified a CD signature that can predict prognostic outcomes of iCCA (CD_UP, n=486 and CD_DOWN, n=308). iCCAs were subgrouped into G1 (positivity for CRP and CDH2, 7%), G3 (positivity for S100P and TFF1, 32%) and G2 (the others, 61%). Prognostic outcomes for overall survival (P=.001) and time to recurrence (P=.017) were the most favourable in G1-iCCAs, intermediate in G2-iCCAs and the worst in G3-iCCAs. Similar result was confirmed in the iCCA set from GSE26566 (n=68). CONCLUSIONS: CD signature was identified to predict the prognosis of iCCA. The combined evaluation of histology of CD and protein expression status of CRP, CDH2, TFF1 and S100P might help subtyping and predicting clinical outcomes of iCCA.


Sujet(s)
Tumeurs des canaux biliaires/génétique , Tumeurs des canaux biliaires/anatomopathologie , Marqueurs biologiques tumoraux/génétique , Différenciation cellulaire/génétique , Cholangiocarcinome/génétique , Cholangiocarcinome/anatomopathologie , Analyse de profil d'expression de gènes/méthodes , Sujet âgé , Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Prolifération cellulaire/génétique , Cholangiocarcinome/composition chimique , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Phénotype , Valeur prédictive des tests , Pronostic , Facteurs de risque , Analyse sur puce à tissus , Transcriptome
13.
Anticancer Res ; 37(10): 5701-5705, 2017 10.
Article de Anglais | MEDLINE | ID: mdl-28982889

RÉSUMÉ

BACKGROUND/AIM: Cancer stem cells (CSC) plays an important role in various kinds of cancers. The aim of this study was to clarify the role of CD44 expression in intrahepatic cholangiocarcinoma (IHCC) as a marker of CSCs. MATERIALS AND METHODS: Thirty-five patients with IHCC patients who underwent hepatectomy were evaluated. CD44 expression was determined immunohistochemically. The patients were divided into a CD44-positive group (n=22) or CD44-negative group (n=13). Clinicopathological variables including prognosis were compared between the two groups. RESULTS: The CD44-positive group had a worse prognosis than the CD44-negative group (5-year survival: 19.3% vs. 55.5%, respectively, p=0.016), although no difference in the background variables was observed. In multivariate analysis, CD44-positivity was identified as an independent prognostic factor (hazard ratio=3.676, p=0.034). CONCLUSION: These data suggest that CD44-positivity might be a candidate CSC marker in IHCC and a prognostic indicator.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/chirurgie , Marqueurs biologiques tumoraux/analyse , Cholangiocarcinome/composition chimique , Cholangiocarcinome/chirurgie , Hépatectomie , Antigènes CD44/analyse , Cellules souches tumorales/composition chimique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/anatomopathologie , Loi du khi-deux , Cholangiocarcinome/mortalité , Cholangiocarcinome/anatomopathologie , Femelle , Hépatectomie/effets indésirables , Hépatectomie/mortalité , Humains , Immunohistochimie , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Cellules souches tumorales/anatomopathologie , Valeur prédictive des tests , Modèles des risques proportionnels , Facteurs de risque , Facteurs temps , Résultat thérapeutique
14.
Am J Surg Pathol ; 41(12): 1630-1641, 2017 Dec.
Article de Anglais | MEDLINE | ID: mdl-28945626

RÉSUMÉ

Differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) from its histologic mimickers, especially metastatic adenocarcinomas of gastric and pancreatic origin, is a great challenge for pathologists. In this study, through bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus, we identified C-reactive protein (CRP) as a candidate marker to differentiate iCCA from other adenocarcinomas and validated its diagnostic performance by immunohistochemistry in a large cohort of clinical samples including 103 iCCAs, 384 other adenocarcinomas, and 34 liver metastases of various origins. The sensitivity and specificity of CRP expression in the diagnosis of iCCA were 75.7% and 91.1% when using tissue microarrays and 93.3% and 88.2% when using whole tissue sections, respectively. We also compared the diagnostic performance of CRP with N-cadherin, a previously reported marker for iCCA. The sensitivity and specificity of N-cadherin were 54.4% and 92.2% when using tissue microarrays and 80.0% and 88.2% when using whole tissue sections, respectively. The sensitivity of CRP was higher than that of N-cadherin, whereas their specificity was similar. CRP expression was associated with mass-forming gross type (P<0.001), absence of perineural invasion (P=0.002), and N-cadherin expression (P<0.001). CRP expression was also associated with better overall survival (P=0.002) and longer recurrence-free time (P=0.032) after surgery. Our study suggests that CRP is a promising immunohistochemical marker to differentiate iCCA from other adenocarcinomas. Compared with N-cadherin, CRP showed higher sensitivity and similar specificity. CRP expression was associated with better prognosis in iCCA.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Protéine C-réactive/analyse , Cholangiocarcinome/composition chimique , Immunohistochimie , Sujet âgé , Antigènes CD/analyse , Tumeurs des canaux biliaires/génétique , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/chirurgie , Marqueurs biologiques tumoraux/génétique , Protéine C-réactive/génétique , Cadhérines/analyse , Cholangiocarcinome/génétique , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/chirurgie , Biologie informatique , Bases de données génétiques , Diagnostic différentiel , Survie sans rechute , Femelle , Humains , Estimation de Kaplan-Meier , Mâle , Adulte d'âge moyen , Valeur prédictive des tests , Reproductibilité des résultats , Facteurs temps , Analyse sur puce à tissus , Résultat thérapeutique
15.
Hum Pathol ; 67: 217-224, 2017 09.
Article de Anglais | MEDLINE | ID: mdl-28823571

RÉSUMÉ

Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.


Sujet(s)
Maladies des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/anatomopathologie , Épithélioma in situ/anatomopathologie , Transformation cellulaire néoplasique/anatomopathologie , Cholangiocarcinome/anatomopathologie , États précancéreux/anatomopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladies des canaux biliaires/chirurgie , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/chirurgie , Marqueurs biologiques tumoraux/analyse , Biopsie , Épithélioma in situ/composition chimique , Épithélioma in situ/chirurgie , Différenciation cellulaire , Prolifération cellulaire , Transformation cellulaire néoplasique/composition chimique , Cholangiocarcinome/composition chimique , Cholangiocarcinome/chirurgie , Évolution de la maladie , Femelle , Hépatectomie , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Grading des tumeurs , Stadification tumorale , États précancéreux/composition chimique , États précancéreux/chirurgie , Études rétrospectives , Charge tumorale
16.
Lab Invest ; 97(9): 1103-1113, 2017 09.
Article de Anglais | MEDLINE | ID: mdl-28581490

RÉSUMÉ

Clinical tissue specimens are useful for pathological diagnosis, which is, in some cases, supported by visualization of biomolecule localization. In general, diagnostic specificity in molecular pathology is increased by the acquisition of a probe to distinguish the modification of isomers. Although glycosylation is one of the candidate modifications in a protein, comparative glycan analysis of disease-associated proteins derived from a single tissue section is still challenging because of the lack of analytical sensitivity. Here we demonstrate a possible method for differential glycoform analysis of an endogenous tumor-associated glycoprotein MUC1 by an antibody-overlay lectin microarray. Tissue sections (5 µm thick) of patients with cholangiocarcinoma (CCA; n=21) and pancreatic ductal adenocarcinoma (PDAC; n=50) were stained with an anti-MUC1 antibody MY.1E12 that was established as a monoclonal antibody recognizing an MUC1 glycosylation isoform with a sialyl-core 1 structure (NeuAcα2-3galactosyl ß1-3-N-acetylgalactosamine). MY.1E12-positive tissue areas (2.5 mm2) were selectively dissected with a laser capture microdissection procedure. The membrane MUC1 was enriched by immunoprecipitation with MY.1E12 and subjected to lectin microarray analysis. Even though the reactivities of MY.1E12 between CCA and PDAC were similar, the lectin-binding patterns varied. We found Maackia amurensis leukoagglutinin and pokeweed lectin distinguished MY.1E12-reactive MUC1 of CCA from that of PDAC. Moreover, MUC1 with M. amurensis hemagglutinin (MAH) reactivity potentially reflected the degree of malignancy. These results were confirmed with MAH-MY.1E12 double fluorescent immunostaining. These glycan changes on MUC1 were detected with high sensitivity owing to the cluster effect of immobilized lectins on a tandem repeat peptide antigen covered with highly dense glycosylation such as mucin. Our approach provides the information to investigate novel glycodynamics in biology, for example, glycoalteration, as well as diseases related to not only MUC1 but also other membrane proteins.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Cholangiocarcinome/composition chimique , Mucine-1/analyse , Mucine-1/composition chimique , Tumeurs du pancréas/composition chimique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/classification , Conduits biliaires/composition chimique , Cholangiocarcinome/classification , Femelle , Glycosylation , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Mucine-1/classification , Mucine-1/métabolisme , Pancréas/composition chimique , Tumeurs du pancréas/classification , Lectines végétales/composition chimique , Lectines végétales/métabolisme , Polyosides/analyse , Polyosides/composition chimique , Polyosides/métabolisme , Tumeurs du pancréas
17.
Hum Pathol ; 65: 92-100, 2017 07.
Article de Anglais | MEDLINE | ID: mdl-28457731

RÉSUMÉ

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and lack of effective treatment, characterized by dense desmoplastic stroma rich in cancer-associated fibroblasts (CAFs), which have been indicated to facilitate tumor progression in several types of human cancer. However, the clinical relevance of CAFs in ICC has not been fully characterized. Here, we evaluated the histological phenotype of CAFs and immunohistochemical expressions of α-SMA, FSP-1, and PDGFRß in 71 ICC cases, and found that immature CAF phenotype was significantly associated with lymph node metastasis (P=.045), advanced TNM stage (P=.025) and poor 5-year overall survival (OS) (38.5% versus 78.6%, P=.015). In addition, α-SMA, FSP-1, and PDGFRß were positively expressed in stromal fibroblasts in 63.4% (45/71), 84.5% (60/71), and 78.9% (56/71) of patients, respectively. Positive expression of α-SMA was correlated with poor differentiation (P=.032); FSP-1 expression in stromal fibroblasts was linked with lymph node metastasis (P=.022) and immature phenotype (P=.048). What's more, positive expression of FSP-1 in cancer cells was observed in 22.5% (16/71) of cases and was correlated with worse 5-year OS (36.4% versus 76.7%, P=.014). Importantly, in multivariate analysis, histological CAF phenotype was an independent prognostic factor for OS in ICC. Our findings demonstrated histological categorization of CAFs was a useful predictor for prognosis, providing new evidence that CAFs play a crucial role in tumor progression and can serve as potential therapeutic targets in ICC.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Fibroblastes associés au cancer/composition chimique , Cholangiocarcinome/composition chimique , Actines/analyse , Tumeurs des canaux biliaires/mortalité , Tumeurs des canaux biliaires/anatomopathologie , Protéines de liaison au calcium/analyse , Fibroblastes associés au cancer/anatomopathologie , Différenciation cellulaire , Loi du khi-deux , Cholangiocarcinome/mortalité , Cholangiocarcinome/secondaire , Femelle , Humains , Immunohistochimie , Estimation de Kaplan-Meier , Métastase lymphatique , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Stadification tumorale , Phénotype , Modèles des risques proportionnels , Récepteur au PDGF bêta/analyse , Facteurs de risque , Protéine S100A4 liant le calcium , Facteurs temps
18.
Hum Pathol ; 62: 232-241, 2017 Apr.
Article de Anglais | MEDLINE | ID: mdl-28232156

RÉSUMÉ

Only a single case report exists in the literature of hepatic adenocarcinoma expressing InhibinA in a young woman, in which the authors proposed it to be a rare variant of intrahepatic cholangiocarcinoma (iCCA). We present novel molecular and histologic findings in our series of three cases occurring in young women and show these tumors may mimic well-differentiated neuroendocrine tumors (NET). Immunohistochemical (IHC) profiling was performed along with a next-generation sequencing (NGS) 47-gene solid tumor panel, and cytogenomic profiling via single-nucleotide polypmorphism microarray. IHC for inhibinA, chromogranin A (ChrA), and synaptophysin (Syn) was surveyed in liver tumors and in fetal liver. Two of the three patients recurred with metastatic disease with two confirmed deaths. Histological patterns present in the tumors included solid, trabecular, organoid, microcystic, and blastemal-like. IHC was positive for cytokeratin 7 in 3/3, cytokeratin 19 in 3/3, inhibinA in 3/3, ChrA in 3/3, Syn in 3/3, Sox9 in 2/3 and HepPar1 in 0/3. NGS was negative for pathogenic mutations. Recurrent cytogenomic abnormalities included gain of 17q, and loss of 6q. InhibinA was strong and diffusely expressed in 0/10 (0%) iCCA, 0/15 (0%) hepatocellular carcinomas (HCC), in the biliary component of 1/4 (25%) combined HCC-iCCA, 0/4 hepatoblastomas, 1/8 (13%) metastatic NET, and in 1/8 fetal liver tissues. We propose a classification of "cholangioblastic variant of intrahepatic cholangiocarcinoma" and molecular pathogenesis for this rare malignancy. Accurate identification on core biopsy is crucial for clinical management as it may mimic neuroendocrine neoplasms.


Sujet(s)
Adénocarcinome/diagnostic , Tumeurs des canaux biliaires/diagnostic , Marqueurs biologiques tumoraux/analyse , Marqueurs biologiques tumoraux/génétique , Cholangiocarcinome/diagnostic , Analyse cytogénétique , Inhibines/analyse , Tumeurs du foie/diagnostic , Techniques de diagnostic moléculaire , Tumeurs neuroendocrines/diagnostic , Adénocarcinome/composition chimique , Adénocarcinome/génétique , Adénocarcinome/secondaire , Adolescent , Adulte , Tumeurs des canaux biliaires/composition chimique , Tumeurs des canaux biliaires/génétique , Tumeurs des canaux biliaires/anatomopathologie , Cholangiocarcinome/composition chimique , Cholangiocarcinome/génétique , Cholangiocarcinome/anatomopathologie , Diagnostic différentiel , Issue fatale , Femelle , Analyse de profil d'expression de gènes , Prédisposition génétique à une maladie , Humains , Immunohistochimie , Tumeurs du foie/composition chimique , Tumeurs du foie/génétique , Tumeurs du foie/anatomopathologie , Tumeurs neuroendocrines/composition chimique , Tumeurs neuroendocrines/génétique , Tumeurs neuroendocrines/anatomopathologie , Phénotype , Polymorphisme de nucléotide simple , Valeur prédictive des tests , Terminologie comme sujet , Résultat thérapeutique
19.
Hum Pathol ; 62: 152-159, 2017 04.
Article de Anglais | MEDLINE | ID: mdl-28089541

RÉSUMÉ

Biliary tumors showing intraductal papillary growth (Pap-BTs) include intraductal papillary neoplasm of the bile duct (IPNB) and papillary cholangiocarcinoma (CC). A differential diagnosis between IPNB and papillary CC currently remains challenging. The aim of the present study is to identify histological features and immunohistochemical markers of malignant potential such as tumor invasion in Pap-BTs. Subjects comprised 37 patients with Pap-BT (intrahepatic and perihilar [proximal], 27: 17 noninvasive and 10 invasive; distal, 10: all invasive). We examined histological features and the expression of p53, enhancer of zeste homolog 2, insulin-like growth factor II mRNA-binding protein 3 (IMP3), and DNA methyltransferase-1 in the intraductal area in Pap-BTs. Noninvasive Pap-BT was characterized by the presence of a low-grade dysplastic area, edematous stroma, and the absence of necrosis. The expression of p53, enhancer of zeste homolog 2, IMP3, and DNA methyltransferase-1 was significantly weaker in noninvasive Pap-BTs than in invasive Pap-BTs (P<.01). Diffuse cytoplasmic IMP3 expression was absent in noninvasive Pap-BTs. IMP3 showed the greatest specificity to predict a presence of invasion. A heatmap demonstrated that proximal noninvasive Pap-BTs and distal Pap-BTs may be completely different. In bile duct biopsies, the expression of IMP3 was the most precise predictor of invasion in Pap-BTs. In conclusion, Pap-BTs may be separated into 3 subgroups: (1) proximal noninvasive Pap-BT, corresponding to IPNB; (2) distal invasive Pap-BT, corresponding to papillary CC; and (3) the remaining Pap-BT including IPNB with associated adenocarcinomas, based on histological and immunohistochemical features. IMP3 may be a useful marker for predicting invasion in Pap-BT.


Sujet(s)
Adénocarcinome papillaire/composition chimique , Tumeurs des canaux biliaires/composition chimique , Conduits biliaires extrahépatiques/composition chimique , Conduits biliaires intrahépatiques/composition chimique , Marqueurs biologiques tumoraux/analyse , Carcinome canalaire/composition chimique , Cholangiocarcinome/composition chimique , Protéines de liaison à l'ARN/analyse , Adénocarcinome papillaire/anatomopathologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/anatomopathologie , Conduits biliaires extrahépatiques/anatomopathologie , Conduits biliaires intrahépatiques/anatomopathologie , Biopsie , Carcinome canalaire/anatomopathologie , Cholangiocarcinome/anatomopathologie , DNA (Cytosine-5-)-methyltransferase 1 , DNA (cytosine-5-)-methyltransferase/analyse , Diagnostic différentiel , Protéine-2 homologue de l'activateur de Zeste/analyse , Femelle , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Invasion tumorale , Valeur prédictive des tests , Protéine p53 suppresseur de tumeur/analyse
20.
Hum Pathol ; 60: 46-57, 2017 02.
Article de Anglais | MEDLINE | ID: mdl-27984121

RÉSUMÉ

Nodular-sclerosing cholangiocarcinoma (NS-CCA) is a common CCA of the intrahepatic large, perihilar, and distal bile ducts. Intraepithelial biliary neoplasms, such as the mucosal extension of carcinoma and preinvasive neoplastic lesions (ie, biliary intraepithelial neoplasia) reportedly occur in the bile ducts around CCA. In the present study, we collectively refer to these intraepithelial lesions as "intraepithelial neoplasms of the bile duct (IENBs)". We examined the IENBs in 57 surgically resected cases of NS-CCA. S100P immunostaining was used to help detect IENBs. The IENBs formed field(s) of continuous neoplastic biliary epithelial cells and showed a flat, micropapillary, or papillotubular configuration. IENBs could be classified into 3 categories based on their atypia: group A (neoplastic but not enough for malignancy), B (neoplastic and sufficiently well differentiated for high-grade dysplasia), and C (overtly malignant and variably differentiated). IENB was found in 31 of 57 cases, with group C the most common (26 cases) followed by group B (22 cases) and group A (16 cases). The expression of cancer-related molecules and MIB-1 index of groups A and B differed from those of invasive CCA, whereas these features of group C were relatively similar to those of invasive CCA. In conclusion, IENB was not infrequently found in NS-CCA and could be classified into 3 grades. Preinvasive lesions (biliary intraepithelial neoplasias) are likely to be found in groups A and B, whereas cancerization would be included in group C. The classification of IENB may be useful for future studies of the preinvasive intraepithelial neoplastic lesions of NS-CCAs.


Sujet(s)
Tumeurs des canaux biliaires/composition chimique , Marqueurs biologiques tumoraux/analyse , Protéines de liaison au calcium/analyse , Épithélioma in situ/composition chimique , Cholangiocarcinome/composition chimique , Cellules épithéliales/composition chimique , Protéines tumorales/analyse , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs des canaux biliaires/anatomopathologie , Tumeurs des canaux biliaires/chirurgie , Biopsie , Épithélioma in situ/anatomopathologie , Épithélioma in situ/chirurgie , Différenciation cellulaire , Cholangiocarcinome/anatomopathologie , Cholangiocarcinome/chirurgie , Évolution de la maladie , Cellules épithéliales/anatomopathologie , Femelle , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Grading des tumeurs , Invasion tumorale , Valeur prédictive des tests , Sclérose , Terminologie comme sujet
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