RESUMEN
Although intraductal oncocytic papillary neoplasm (IOPN) was considered distinct from the intraductal papillary neoplasm of the pancreas, the oncocytic histologic type remained as a subtype of intraductal papillary neoplasms of the bile duct (IPNBs) with gastric, intestinal, and pancreatobiliary types based on the fifth edition of the WHO classification. To test the characteristics of the oncocytic type of IPNBs, the histopathologic, immunohistochemical (Hep Par-1 and CD117), and clinical characteristics of 13 oncocytic type were compared with 114 others (15 gastric, 39 pancreatobiliary, and 60 intestinal) IPNB types. The oncocytic type, which occupied about 9% of IPNBs, was more frequent in females (p < 0.05) and larger (mean, 5.3 vs. 3.6 cm; p < 0.002) than other IPNB types. Immunohistochemically, the oncocytic type had more frequent combined Hep Par-1 and CD117 expression than other IPNB types (all p < 0.05). The recurrence-free survival rate for patients with the oncocytic type (5-year survival, 100%) was significantly higher (p = 0.015) than for those with other histologic types (59.9%). The oncocytic type had distinct histopathologic, immunohistochemical, and survival outcomes from other IPNBs. Therefore, it can be separated from other IPNB types and classified as one independent entity, similar to IOPN of the pancreas.
Asunto(s)
Neoplasias de los Conductos Biliares , Biomarcadores de Tumor , Inmunohistoquímica , Humanos , Femenino , Masculino , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/química , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/patología , Supervivencia sin Enfermedad , Carcinoma Papilar/patología , Carcinoma Papilar/mortalidad , Carcinoma Papilar/química , AdultoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares , Biomarcadores de Tumor , Proteínas de Unión al Calcio , Colangiocarcinoma , Inmunohistoquímica , Osteopontina , Humanos , Colangiocarcinoma/patología , Colangiocarcinoma/clasificación , Colangiocarcinoma/mortalidad , Colangiocarcinoma/química , Colangiocarcinoma/diagnóstico , Osteopontina/análisis , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/clasificación , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Anciano , Estudios Retrospectivos , Proteínas de Unión al Calcio/análisis , Adulto , Anciano de 80 o más Años , Proteínas de Neoplasias/análisis , Valor Predictivo de las Pruebas , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Triterpenos/farmacología , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Colangiocarcinoma/química , Colangiocarcinoma/patología , Humanos , Espectroscopía Infrarroja por Transformada de Fourier/instrumentación , Sincrotrones/instrumentación , Ácido UrsólicoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/química , Carcinoma Ductal Pancreático/química , Colangiocarcinoma/química , Osteonectina/análisis , Neoplasias Pancreáticas/química , Células del Estroma/química , Adulto , Anciano , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Proliferación Celular , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Estudios Transversales , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Osteonectina/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Células del Estroma/patología , Factor A de Crecimiento Endotelial Vascular/análisisAsunto(s)
Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Neurilemoma/patología , Anciano , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Conductos Biliares Intrahepáticos/química , Conductos Biliares Intrahepáticos/diagnóstico por imagen , Biomarcadores de Tumor/análisis , Femenino , Hepatectomía , Humanos , Neurilemoma/química , Neurilemoma/diagnóstico por imagen , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Colangiocarcinoma/genética , Perfilación de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Complejas y Mixtas/genética , Nestina/genética , Transcriptoma , Asia , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/clasificación , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/patología , Colangiocarcinoma/química , Colangiocarcinoma/clasificación , Colangiocarcinoma/patología , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/química , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/patología , Masculino , Neoplasias Complejas y Mixtas/química , Neoplasias Complejas y Mixtas/clasificación , Neoplasias Complejas y Mixtas/patología , Nestina/análisis , Valor Predictivo de las Pruebas , Pronóstico , Regulación hacia ArribaRESUMEN
Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P<0.001). All patients with ICPN lacked lymphovascular invasion and nodal metastasis, while these features were occasionally observed in patients with papillary or nonpapillary GBC (13% to 59%). ICPNs were less advanced than papillary and nonpapillary GBCs (P<0.001) with all cases of ICPNs being recurrence-free. Whole-exome and Sanger sequencing identified somatic mutations in STK11 (a causative gene of Peutz-Jegher syndrome; n=3), CTNNB1 (n=2), and APC (a gene of familial adenomatous polyposis; n=1) in ICPNs, while those alterations were exceptional in papillary and nonpapillary GBCs. ICPNs more commonly showed cytoplasmic and/or nuclear expressions of ß-catenin than papillary and nonpapillary GBCs. In conclusion, the histology-based classification of gallbladder papillary neoplasms is useful for identifying ICPNs that share clinicopathologic features with the pancreatic counterpart. ICPNs meeting the criteria were genetically distinct from papillary and nonpapillary GBCs, with STK11, CTNNB1, and APC being identified as major driver genes for ICPNs.
Asunto(s)
Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/patología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/genética , Secuenciación del Exoma , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/patología , Quinasas de la Proteína-Quinasa Activada por el AMP , Adenocarcinoma Papilar/química , Adenocarcinoma Papilar/terapia , Proteína de la Poliposis Adenomatosa del Colon/genética , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/terapia , Biomarcadores de Tumor/análisis , Biopsia , Diagnóstico Diferencial , Femenino , Neoplasias de la Vesícula Biliar/química , Neoplasias de la Vesícula Biliar/terapia , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Valor Predictivo de las Pruebas , Proteínas Serina-Treonina Quinasas/genética , Factores de Riesgo , Resultado del Tratamiento , beta Catenina/genéticaRESUMEN
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.
Asunto(s)
5'-Nucleotidasa/análisis , Neoplasias de los Conductos Biliares/química , Sistema Biliar/química , Neoplasias Hepáticas/química , Hígado/química , Páncreas/química , Neoplasias Pancreáticas/química , 5'-Nucleotidasa/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Colangiocarcinoma/química , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Transición Epitelial-Mesenquimal , Proteínas Ligadas a GPI/análisis , Proteínas Ligadas a GPI/antagonistas & inhibidores , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , PronósticoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/química , Biomarcadores de Tumor/análisis , Colangiocarcinoma/química , Proteínas Nucleares/análisis , Factores de Transcripción/análisis , Proteínas Supresoras de Tumor/análisis , Ubiquitina Tiolesterasa/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Biomarcadores de Tumor/genética , Proteínas de Unión al Calcio/análisis , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangiocarcinoma/cirugía , Proteínas de Unión al ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Hepatectomía/métodos , Humanos , Inmunohistoquímica , Hibridación in Situ , Laparoscopía , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Estudios Retrospectivos , Factores de Tiempo , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/química , Biomarcadores de Tumor/análisis , Colangiocarcinoma/química , Proteína del Locus del Complejo MDS1 y EV11/análisis , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Progresión de la Enfermedad , Femenino , Hepatectomía , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/patología , Carcinoma de Células Escamosas/patología , Colangiocarcinoma/patología , Neoplasias de Cabeza y Cuello/patología , Neoplasias Laríngeas/patología , Neoplasias Primarias Múltiples/patología , Obesidad/complicaciones , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Biomarcadores de Tumor/análisis , Biopsia , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/diagnóstico por imagen , Colangiocarcinoma/química , Colangiocarcinoma/diagnóstico por imagen , Trastornos de Deglución/etiología , Progresión de la Enfermedad , Resultado Fatal , Neoplasias de Cabeza y Cuello/química , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Ronquera/etiología , Humanos , Inmunohistoquímica , Neoplasias Laríngeas/química , Neoplasias Laríngeas/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/química , Neoplasias Primarias Múltiples/diagnóstico por imagen , Obesidad/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Tomografía Computarizada por Rayos XAsunto(s)
Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/secundario , Neoplasias Faciales/secundario , Neoplasias Cutáneas/secundario , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Biomarcadores de Tumor/análisis , Biopsia , Colangiocarcinoma/química , Colangiocarcinoma/diagnóstico por imagen , Neoplasias Faciales/química , Resultado Fatal , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/química , Tomografía Computarizada por Rayos XRESUMEN
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.
Asunto(s)
Neoplasias de los Conductos Biliares/genética , Biomarcadores de Tumor/genética , Colangiocarcinoma/genética , Amplificación de Genes , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/virología , Biomarcadores de Tumor/análisis , China , Colangiocarcinoma/química , Colangiocarcinoma/patología , Colangiocarcinoma/virología , Femenino , Predisposición Genética a la Enfermedad , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Pronóstico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/análisis , Translocación GenéticaRESUMEN
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.
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Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/genética , Diferenciación Celular/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Perfilación de la Expresión Génica/métodos , Anciano , Neoplasias de los Conductos Biliares/química , Biomarcadores de Tumor/análisis , Proliferación Celular/genética , Colangiocarcinoma/química , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Análisis de Matrices Tisulares , TranscriptomaRESUMEN
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.
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Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/cirugía , Biomarcadores de Tumor/análisis , Colangiocarcinoma/química , Colangiocarcinoma/cirugía , Hepatectomía , Receptores de Hialuranos/análisis , Células Madre Neoplásicas/química , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Distribución de Chi-Cuadrado , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Femenino , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Células Madre Neoplásicas/patología , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: To compare the cells of mucosal extension (ME) and radial invasion (RI) in hilar cholangiocarcinoma (HCCA) for optimal resection. MATERIALS AND METHODS: Forty-six patients underwent surgery for HCCA between 1992 and 2004. Immunohistochemical expressions of p53, Ki-67, matrix metalloproteinase-7 (MMP7), mucin 1 (MUC1), and E-cadherin were assessed at five different sites of the tumour and compared between the recurrence and non-recurrence groups. RESULTS: Expression of E-cadherin was significantly lower in RI cells than in ME cells, and that of MMP7 and MUC1 was significantly higher in RI cells than in ME cells. Ki-67 expression was higher in ME cells than in RI cells. During the 11-year follow-up, recurrence in patients with R0 resection was associated with significantly lower E-cadherin, higher MMP7, and higher Ki-67 expression. CONCLUSION: Removal of as many RI cells as possible should be a priority in resection of HCCA, followed by removal of ME cells. E-Cadherin appears to be associated with recurrence of HCCA.
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Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/análisis , Inmunohistoquímica , Tumor de Klatskin/química , Tumor de Klatskin/patología , Membrana Mucosa/patología , Anciano , Antígenos CD , Neoplasias de los Conductos Biliares/cirugía , Cadherinas/análisis , Femenino , Humanos , Antígeno Ki-67/análisis , Tumor de Klatskin/cirugía , Masculino , Metaloproteinasa 7 de la Matriz/análisis , Persona de Mediana Edad , Mucina-1/análisis , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisisRESUMEN
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.
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Neoplasias de los Conductos Biliares/química , Biomarcadores de Tumor/análisis , Proteína C-Reactiva/análisis , Colangiocarcinoma/química , Inmunohistoquímica , Anciano , Antígenos CD/análisis , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/cirugía , Biomarcadores de Tumor/genética , Proteína C-Reactiva/genética , Cadherinas/análisis , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangiocarcinoma/cirugía , Biología Computacional , Bases de Datos Genéticas , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Factores de Tiempo , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
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.
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Enfermedades de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/patología , Carcinoma in Situ/patología , Transformación Celular Neoplásica/patología , Colangiocarcinoma/patología , Lesiones Precancerosas/patología , Anciano , Anciano de 80 o más Años , Enfermedades de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/cirugía , Biomarcadores de Tumor/análisis , Biopsia , Carcinoma in Situ/química , Carcinoma in Situ/cirugía , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica/química , Colangiocarcinoma/química , Colangiocarcinoma/cirugía , Progresión de la Enfermedad , Femenino , Hepatectomía , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Lesiones Precancerosas/química , Lesiones Precancerosas/cirugía , Estudios Retrospectivos , Carga TumoralRESUMEN
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.
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Neoplasias de los Conductos Biliares/química , Colangiocarcinoma/química , Mucina-1/análisis , Mucina-1/química , Neoplasias Pancreáticas/química , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/clasificación , Conductos Biliares/química , Colangiocarcinoma/clasificación , Femenino , Glicosilación , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mucina-1/clasificación , Mucina-1/metabolismo , Páncreas/química , Neoplasias Pancreáticas/clasificación , Lectinas de Plantas/química , Lectinas de Plantas/metabolismo , Polisacáridos/análisis , Polisacáridos/química , Polisacáridos/metabolismo , Neoplasias PancreáticasRESUMEN
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.