RESUMEN
OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.
Asunto(s)
Carcinoma Ductal Pancreático , Colangiocarcinoma , Inmunohistoquímica , Mucina 4 , Neoplasias Pancreáticas , Humanos , Mucina 4/metabolismo , Mucina 4/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangre , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/sangre , Adulto , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/genética , Pancreatitis Crónica/diagnóstico , Pancreatitis Crónica/sangre , Estudios de Casos y Controles , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/patología , Relevancia ClínicaRESUMEN
BACKGROUND: Periampullary cancer (PAC) is highly aggressive with no effective adjuvant therapy or prognostic markers. Recently, poly (ADP-ribose) polymerase-1 (PARP-1) has emerged as a target in solid cancers, and its relationship with epithelial-mesenchymal transition (EMT) has been observed. However, the relationship between PARP-1 and EMT in PAC has not explored well. MATERIALS AND METHODS: We assessed the prognostic significance of PARP-1 in 190 PACs patients and correlated it with EMT markers, including FGF8, FGFR4, MMP2, MMP3, Snail, and ZEB1. Immunohistochemistry for PARP-1 and EMT markers was performed using a tissue microarray. RESULTS: PARP-1 and FGF8 expression were associated with better survival unlike other solid cancers ( P = 0.006 and P = 0.003), and MMP3 and ZEB1 expression were associated with poor prognosis in multivariate and survival analyses ( P = 0.009 and P < 0.001). In addition, PARP-1 is related negatively to Snail but not related with other EMT markers, implying an independent mechanism between PARP-1 and EMT in PACs. PARP-1 and FGF8 are independent good survival markers in PACs unlike other solid cancers. CONCLUSIONS: PARP-1 and FGF8 in PACs could not be related to the EMT pathway but must be rather understood in light of similar cancer-protective roles. Further studies are required on EMT-associated immune markers in PACs.
Asunto(s)
Biomarcadores de Tumor , Transición Epitelial-Mesenquimal , Neoplasias Pancreáticas , Poli(ADP-Ribosa) Polimerasa-1 , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pronóstico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Inmunohistoquímica , Adulto , Ampolla Hepatopancreática/patología , Ampolla Hepatopancreática/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Anciano de 80 o más Años , Estimación de Kaplan-Meier , Análisis de Matrices Tisulares , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/mortalidad , Análisis Multivariante , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genéticaRESUMEN
Mixed-type ampullary cancer is a distinct subtype of ampullary cancer that manifests a merging of the biological characteristics of both intestinal and pancreaticobiliary subtypes. The absence of established cell lines specific to this subtype has resulted in a concomitant scarcity of research on its tumorigenic mechanisms and the development of novel therapeutic modalities. The present study achieved the successful establishment of a novel mixed-type ampullary cancer cell line, designated DPC-X4 through primary culture techniques. Subsequent analyses pertaining to phenotypic characteristics, molecular profiling, biomarker identification, and histological features validated the DPC-X4 cell line as a potent model for delineating the pathogenesis of mixed-type ampullary cancer and facilitating the development of new pharmacological agents. This newly established cell line was subjected to continuous cultivation for 1 year, with stable passaging for over 50 generations. Notably, the DPC-X4 cell line manifested typical morphological features associated with epithelial tumors. Furthermore, the population doubling time for the DPC-X4 cell line was determined at 70 h. Short tandem repeat (STR) analysis confirmed that the DPC-X4 cell line exhibited a high genetic concordance with the primary tumor from the patient. Karyotypic profiling indicated an abnormal sub-triploid karyotype, with representative karyotypes of 57, XXY inv (9), 14p + , 15p + , der (17), + mar. The DPC-X4 cell line demonstrated a high capacity for efficient organoid formation under suspension culture conditions. In addition, the subcutaneous inoculation of DPC-X4 cells into NXG mice led to the formation of xenografted tumors. The results of drug sensitivity testing indicated that DPC-X4 cells were sensitive to paclitaxel and resistant to oxaliplatin, 5-fluorouracil, and gemcitabine. Immunohistochemistry revealed positive expression of CK7, CK19, and CK20 in DPC-X4 cells, while CDX2 demonstrated negative expression. In addition, positive expression of E-cadherin and vimentin was identified in DPC-X4 cells, with a proliferation index indicated by Ki-67 at 70%. The findings of our study establish DPC-X4 as a novel mixed-type ampullary cancer cell line, which can serve as a potential experimental model for exploring the pathogenesis of ampullary cancer and the development of therapeutic drugs.
Asunto(s)
Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco , Neoplasias , Humanos , Animales , Ratones , Biomarcadores de Tumor/metabolismo , Ampolla Hepatopancreática/química , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/patología , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias/patología , Línea Celular , Línea Celular TumoralRESUMEN
BACKGROUND/AIM: Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection. PATIENTS AND METHODS: This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses. RESULTS: BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors. CONCLUSION: The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores.
Asunto(s)
Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/cirugía , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirugía , Inflamación/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/patología , Ampolla Hepatopancreática/cirugía , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Neoplasias del Sistema Biliar/metabolismo , Neoplasias del Sistema Biliar/mortalidad , Biomarcadores de Tumor/metabolismo , Proteína C-Reactiva/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidad , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias del Conducto Colédoco/cirugía , Femenino , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Inflamación/metabolismo , Japón/epidemiología , Tumor de Klatskin/diagnóstico , Tumor de Klatskin/metabolismo , Tumor de Klatskin/mortalidad , Tumor de Klatskin/cirugía , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Pronóstico , Proyectos de Investigación , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatic and periampullary carcinoma are aggressive tumours where preoperative assessment is challenging. Disseminated tumour cells (DTC) in the bone marrow (BM) are associated with impaired prognosis in a variety of epithelial cancers. In a cohort of patients with presumed resectable pancreatic and periampullary carcinoma, we evaluated the frequency and the potential prognostic impact of the preoperative presence of DTC, defined as cytokeratin-positive cells detected by immunocytochemistry (ICC). METHODS: Preoperative BM samples from 242 patients selected for surgical resection of presumed resectable pancreatic and periampullary carcinoma from 09/2009 to 12/2014, were analysed for presence of CK-positive cells by ICC. The median observation time was 21.5 months. Overall survival (OS) and disease-free survival (DFS) were calculated by Kaplan-Meier and Cox regression analysis. RESULTS: Successful resections of malignant tumours were performed in 179 of the cases, 30 patients resected had benign pancreatic disease based on postoperative histology, and 33 were deemed inoperable intraoperatively due to advanced disease. Overall survival for patients with resected carcinoma was 21.1 months (95% CI: 18.0-24.1), for those with benign disease OS was 101 months (95% CI: 69.4-132) and for those with advanced disease OS was 8.8 months (95% CI: 4.3-13.3). The proportion of patients with detected CK-positive cells was 6/168 (3.6%) in resected malignant cases, 2/31 (6.5%) in advanced disease and 4/29 (13.8%) in benign disease. The presence of CK-positive cells was not correlated to OS or DFS, neither in the entire cohort nor in the subgroup negative for circulating tumour cells (CTC). CONCLUSIONS: The results indicate that CK-positive cells may be present in both patients with malignant and benign diseases of the pancreas. Detection of CK-positive cells was not associated with differences in prognosis for the entire cohort or any of the subgroups analysed. TRIAL REGISTRATION: clinicaltrials.gov ( NCT01919151 ).
Asunto(s)
Adenocarcinoma/patología , Ampolla Hepatopancreática/patología , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias Duodenales/patología , Queratinas/metabolismo , Neoplasias Pancreáticas/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/cirugía , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/cirugía , Neoplasias Duodenales/metabolismo , Neoplasias Duodenales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirugía , Pronóstico , Tasa de SupervivenciaRESUMEN
It is unclear to what extent patients with pancreatic cancer have cachexia and had a dietetic consult for nutritional support. The aim was to assess the prevalence of cachexia, dietitian consultation, and overall survival in these patients. This prospective multicenter cohort study included patients with pancreatic cancer, who participated in the Dutch Pancreatic Cancer Project and completed patient reported outcome measures (2015-2018). Additional data were obtained from the Netherlands Cancer Registry. Cachexia was defined as self-reported >5% body weight loss, or >2% in patients with a BMI <20 kg/m2 over the past half year. The Kaplan-Meier method was used to analyze overall survival. In total, 202 patients were included from 18 centers. Cachexia was present in 144 patients (71%) and 81 of those patients (56%) had dietetic consultation. Cachexia was present in 63% of 94 patients who underwent surgery, 77% of 70 patients who received palliative chemotherapy and 82% of 38 patients who had best supportive care. Dietitian consultation was reported in 53%, 52%, and 71%, respectively. Median overall survival did not differ between patients with and without cachexia, but decreased in those with severe weight loss (12 months (IQR 7-20) vs. 16 months (IQR 8-31), p = 0.02), as compared to those with <10% weight loss during the past half year. Two-thirds of patients with pancreatic cancer present with cachexia of which nearly half had no dietetic consultation. Survival was comparable in patients with and without cachexia, but decreased in patients with more severe weight loss.
Asunto(s)
Ampolla Hepatopancreática/patología , Caquexia/dietoterapia , Neoplasias del Conducto Colédoco/metabolismo , Dietética/métodos , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/metabolismo , Anciano , Índice de Masa Corporal , Caquexia/etiología , Caquexia/mortalidad , Caquexia/patología , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias del Conducto Colédoco/patología , Neoplasias del Conducto Colédoco/terapia , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Países Bajos/epidemiología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Estudios Prospectivos , Derivación y Consulta , Tasa de SupervivenciaRESUMEN
BACKGROUND: Periampullary cancers (PAC) including pancreatic, ampulla of Vater (AOV), and common bile duct (CBD) cancers are highly aggressive with a lack of useful prognostic markers beyond T stage. However, T staging can be biased due to the anatomic complexity of this region. Recently, several markers related to cancer stem cells and epithelial-mesenchymal transition (EMT) such as octamer transcription factor-4 (Oct4) and fibroblast growth factor receptor 1 (FGFR1) respectively, have been proposed as new promising markers in other solid cancers. The aim of this study was to assess the expression and prognostic significance of stem cell/EMT markers in PACs. METHODS: Formalin-fixed, paraffin-embedded tissues of surgically excised PACs from the laboratory archives from 1998 to 2014 were evaluated by immunohistochemical staining for stem cell/EMT markers using tissue microarray. The clinicopathologic parameters were documented and statistically analyzed with the immunohistochemical findings. Survival and recurrence data were collected and analyzed. RESULTS: A total of 126 PAC cases were evaluated. The average age was 63 years, with 76 male and 50 female patient samples. Age less than 74 years, AOV cancers, lower T & N stage, lower tumor size, no lymphatic, vascular, perineural invasion and histologic well differentiation, intestinal type, no fibrosis, severe inflammation were significantly associated with the better overall survival High expression levels of FGFR1 as well as CK20, CDX2, and VEGF were significantly related to better overall survival, while other stem cell markers were not related. Similar findings were observed for tumor recurrence using disease-free survival. CONCLUSIONS: In addition to other clinicopathologic parameters, severe fibrosis was related to frequent tumor recurrence, and high FGFR1 expression was associated with better overall survival. Histologic changes such as extensive fibrosis need to be investigated further in relation to EMT of PACs.
Asunto(s)
Ampolla Hepatopancreática/patología , Neoplasias del Conducto Colédoco/metabolismo , Transición Epitelial-Mesenquimal , Células Madre Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias del Conducto Colédoco/patología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , PronósticoRESUMEN
BACKGROUND/AIM: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) plays an important role in the adhesion, invasion, and metastasis of tumor cells. Although emerging evidence suggests that IMP3 promotes tumor progression in several malignancies, the expression of IMP3 and its prognostic implication in adenocarcinoma of the ampulla of Vater (AVAC) has not been clarified to date. MATERIALS AND METHODS: The IMP3 expression status in 87 AVAC tissues was examined using immunostaining, and its association with various clinicopathological features and outcome of patients with AVAC was investigated. RESULTS: The vast majority (87.4%) of AVAC cases displayed at least focal cytoplasmic and membranous IMP3 immunoreactivity in tumor cells, whereas IMP3 expression was consistently absent from normal biliary epithelial cells. Tumor-specific IMP3 expression was associated with submucosal and pancreatic invasion, which were not identified in the corresponding hematoxylin and eosin-stained slides. This finding led to up-staging of the pathological tumor stage in two cases of well-differentiated AVAC. In addition, high IMP3 expression was significantly associated with a poorly differentiated histology (p=0.026). Survival analyses revealed that high IMP3 expression independently predicted shorter recurrence-free (p=0.003) and overall (p=0.029) survival. CONCLUSION: Our study demonstrated tumor-specific IMP3 expression in AVAC, which will be helpful in determining invasion depth and tumor extent in patients with well-differentiated tumors, as well as indicating worse survival of patients with AVAC. Our data highlight IMP3 expression status as a potential diagnostic and prognostic marker for AVAC.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Ampolla Hepatopancreática/patología , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/mortalidad , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adulto , Anciano , Biomarcadores de Tumor , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/metabolismo , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Proteínas de Unión al ARN/genética , Carga TumoralRESUMEN
BACKGROUND: Expression of High-Mobility Group Box 1 (HMGB1), a multifunctional protein involved in DNA function as well as cell proliferation, inflammation, and the immune response, has been reported to be prognostic in several types of malignancies. However, the prognostic value of HMGB1 in ampullary cancer has not been studied. METHODS: Patients with adenocarcinoma of the ampulla of Vater who underwent R0 resection with pancreaticoduodenectomy between 2001 and 2011 were included in the present multi-institutional study. The degree of HMGB1 expression was examined in each resected specimen by immunohistochemical staining. RESULTS: A total of 101 patients were enrolled of which, 79 patients were eligible. High expression of HMGB1 was observed in 31 (39%) patients. Blood loss, transfusion, tumor stage, nodal status, and HMGB1 expression were identified as predictors with univariate analysis. Multivariate analysis showed that transfusion, lymph-node metastasis, and high HMGB1 expression were independent predictors of poor overall survival. Subgroup analysis showed that high HMGB1 expression was predictive, especially in patients who did not receive adjuvant chemotherapy. CONCLUSIONS: High HMGB1 expression is an independent predictor of poor prognosis in patients with adenocarcinoma of the ampulla of Vater not treated with adjuvant chemotherapy.
Asunto(s)
Adenocarcinoma/mortalidad , Ampolla Hepatopancreática/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Proteína HMGB1/metabolismo , Pancreaticoduodenectomía/mortalidad , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/patología , Ampolla Hepatopancreática/cirugía , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias del Conducto Colédoco/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The primary malignancy of liver, known as hepatocellular carcinoma (HCC), comprises 9% of all hepatobiliary carcinomas. A steady rise has also been observed in adenocarcinoma (ADC) of the liver and ampullary carcinoma (AMC), ascending to 0.5% of gastrointestinal malignancies. Hepatobiliary carcinomas consist of 13% of all cancer occurrences worldwide. Purinergic receptor-based signaling holds the therapeutic potential based on its role in cell proliferation of several carcinomas. An altered ATP concentration in nanomoles may lead towards crucial changes in cancer growth patterns in liver tissue. A total of 40 tissue samples were collected (20 samples of HCC, 10 samples of ADC, and 10 samples of AMC) from patients that underwent surgery. P2X4 and P2X7 receptors exhibited significantly increased expression in HCC, ADC, and AMC samples as compared with the control tissue samples. While ADC and AMC samples showed higher expression of P2X4 and P2X7 than the control, statistically, HCC samples exhibited the most significant expression of both P2X4 and P2X7 receptors than control tissues. It may be inferred that higher expression of P2X4 and P2X7 receptors is significantly associated with the upregulated cellular stress leading to inflammation and it is plausible that both these receptors may be used in diagnostic, prognostic, and therapeutic tools for carcinoma studies in the future.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Adenocarcinoma/patología , Neoplasias del Conducto Colédoco/patología , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias Hepáticas/patología , Masculino , PakistánRESUMEN
BACKGROUND: Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. METHODS: In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. RESULTS: Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. CONCLUSIONS: Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.
Asunto(s)
Adenocarcinoma/genética , Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco/genética , Neoplasias Duodenales/genética , Adenocarcinoma/clasificación , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Factor de Transcripción CDX2/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias del Conducto Colédoco/clasificación , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Neoplasias Duodenales/clasificación , Neoplasias Duodenales/metabolismo , Neoplasias Duodenales/patología , Femenino , Humanos , Inmunohistoquímica , Queratina-20/metabolismo , Queratina-7/metabolismo , Masculino , Persona de Mediana Edad , Mucina 5AC/metabolismo , Mucina-1/metabolismo , Mucina 2/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
OBJECTIVES: To investigate the function of immunomarkers CK7, CK20, CK17, CDX2, MUC1, and MUC2 in the identification of primary ampullary carcinoma mixed subtype. METHODS: Forty-two cases of primary ampullary carcinoma were performed by immunohistochemical studies. The correlation between the mixed subtype and the other two subtypes and patient survival data was analyzed using the SPSS 16.0 statistical software. RESULTS: Among 42 cases, 12 (28.6%) cases were classified as mixed subtype, which showed variable expression patterns: 91.7% (11/12) for CK7, 83.3% (10/12) for CK20; 66.7% (8/12) for CK17, CDX2, and MUC1; and 50% (6/12) for MUC2. Ten (83.3%) mixed types coexpressed four or more immunomarkers. Eight (19%) intestinal subtypes mainly showed a positive expression of CK20, CDX2, and MUC2. Twenty-two (52.4%) pancreaticobiliary subtypes showed a positive expression of CK7, MUC1, and CK17. Stages III and IV diseases in mixed subtype (25%) and intestinal subtype (25%) were less than pancreaticobiliary subtype(63.6%) (p = 0.039). Follow-up data appeared to show a better survival rate for patients with mixed subtype than those with pancreaticobiliary subtypes. CONCLUSION: Immunohistochemical staining provided a more reliable means of diagnosing mixed ampulla carcinoma. Accurate subtyping of ampullary carcinoma is clinically important to select effective chemotherapy regimens and to assess disease prognosis.
Asunto(s)
Adenocarcinoma/patología , Ampolla Hepatopancreática/patología , Anticuerpos Monoclonales/inmunología , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/clasificación , Neoplasias del Conducto Colédoco/patología , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/inmunología , Ampolla Hepatopancreática/metabolismo , Biomarcadores de Tumor/inmunología , Neoplasias del Conducto Colédoco/inmunología , Neoplasias del Conducto Colédoco/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVES: To investigate immunohistochemical predictors for intestinal and pancreatobiliary types of adenocarcinoma of ampulla of Vater and identify clinicopathological characteristics associated with the histological types and patient survival. METHODS: Immunohistochemical markers included MUC1, MUC2, MUC5AC, CDX2, CK7, and CK20. The data were analyzed by univariate and multivariate methods. The two-step cluster method was used to determine the best immunohistochemical markers to discriminate the intestinal from the pancreatobiliary type. RESULTS: This study identified 9 (33.3%) intestinal and 21 (66.7%) pancreatobiliary tumors. CK7 and CDX2 achieved the highest value (= 1) as predictor markers, while CK20, MUC1, and MUC2 showed degrees of importance equal to 0.77, 0.71, and 0.68, respectively. MUC5AC did not reach 0.50 of importance. In the univariate analysis, lymph node involvement, staging (TNM), and angiolymphatic and perineural invasions were associated with histological types. The independent clinicopathological variable in the multivariate model to predict the histological type was angiolymphatic invasion (p = 0.005), OR = 17 (95% CI 2.33 to 123.83). The final model showed positive nodes (N1) associated with shorter survival (HR = 9.5; p = 0.006). Overall survival at 12, 36, and 60 months was 88.5, 67.0, and 47.6%, respectively. CONCLUSIONS: CDX2 and CK7 were the immunohistochemical markers that best discriminated the intestinal from the pancreatobiliary type. Lymph node involvement had a high impact on survival and proved to be more frequent in the pancreatobiliary type.
Asunto(s)
Adenocarcinoma/metabolismo , Ampolla Hepatopancreática/patología , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/patología , Neoplasias del Conducto Colédoco/metabolismo , Inmunohistoquímica/métodos , Proteínas de Neoplasias/metabolismo , Adenocarcinoma/diagnóstico , Adulto , Anciano , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Factor de Transcripción CDX2/metabolismo , Neoplasias del Conducto Colédoco/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Queratinas/metabolismo , Masculino , Persona de Mediana Edad , Mucinas/metabolismo , PronósticoRESUMEN
OBJECTIVE: To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC). BACKGROUND: The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders. METHODS: We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma (KRAS), neuroblastoma RAS (NRAS), B rapidly accelerated fibrosarcoma (BRAF), TP53, and 4 membrane erythroblastosis oncogene B (ERBB) receptor tyrosine kinases (EGFR-ERBB1, HER2-ERBB2, HER3-ERBB3, HER4-ERBB4) amenable to pharmacological inhibition. Moreover, we evaluated mutations in 16 key components of rat sarcoma (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein 53 (P53), transforming growth factor beta (TGF-ß), and wingless/integrated (WNT) pathways, recently associated to AVC by whole-exome sequencing. RESULTS: TP53 and KRAS were mutated in 41% and 35% of cases, respectively, and emerged as independent prognostic factors together with tumor stage and regardless of the histotype (TP53: P = 0.0006; KRAS: P = 0.0018; stage IIB: P = 0.0117; stage III-IV: P = 0.0020). ERBB, WNT and PI3K pathway genes were mutated in 37.5% of cases. CONCLUSIONS: KRAS and TP53 mutations are negative predictors of survival in AVCs, regardless of histotype. Potentially actionable mutations in ERBB, WNT, and PI3K signaling pathway genes are present in 37.5% of all cases. These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling.
Asunto(s)
Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Receptor ErbB-3/genética , Proteína p53 Supresora de Tumor/genética , Vía de Señalización Wnt/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/metabolismo , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Receptor ErbB-3/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Ampullary carcinoma or cancer of the ampulla of Vater is a rare malignancy with a high recurrence rate. Although cost-effective biomarkers, such as neutrophil-to-lymphocyte ratio (NLR), have been investigated in other cancers for predicting postoperative prognosis in patients, studies on the role of NLR in ampullary cancer are scarce. Here we aimed to evaluate the prognostic significance of preoperative NLR in patients with operable ampullary carcinoma. We retrospectively reviewed 87 patients who underwent pancreaticoduodenectomy for the treatment of ampullary carcinoma between December 1999 and April 2014. The association between NLR and prognosis (overall survival [OS] and disease-free survival [DFS]) was evaluated. Possible correlations between NLR and clinicopathological features were also assessed. The 5-year DFS and OS rates after surgery in patients with ampullary carcinoma were 51% and 63%, respectively. A high NLR (≥3.0) was found in 40 patients. The NLR was a significant prognostic factor for both OS and DFS. Multivariate analysis revealed a significantly worse OS in patients with positive surgical margins and NLR ≥3 (p = 0.001). Patients with T3-T4 stage (p = 0.029) and NLR ≥3 (p = 0.043) had a lower DFS. Patients with a high NLR had a significantly worse Eastern Cooperative Oncology Group performance score. Preoperative NLR is an independent and significant predictive factor of prognosis in patients with ampullary carcinoma. An elevated pretreatment NLR (e.g., NLR ≥3) may be considered as a biomarker for poor prognosis in patients with ampullary carcinoma.
Asunto(s)
Ampolla Hepatopancreática/patología , Carcinoma/diagnóstico , Neoplasias del Conducto Colédoco/diagnóstico , Linfocitos/citología , Neutrófilos/citología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Carcinoma/cirugía , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Inflamación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Recently, immunohistochemistry-based classifications of ampullary carcinomas have been proposed (Ang and colleagues [PMID: 24832159]; Chang and colleagues [PMID: 23439753]). In this study, the prognostic value of Ang/Chang panel markers (CK20, MUC1, MUC2, CDX2) as well as other markers (CK7, MUC5AC, and MUC6) were tested on full-faced sections of 136 ampullary carcinoma resections with substantial (>5 mm) invasion. Immunohistochemistry was correlated with both histologic classification (intestinal [INT], pancreatobiliary [PB], or nontubular based on ≥3/5 observer agreement) and clinical outcome. No prognostic correlation was found with MUC1, CDX2, MUC2 or CK20 despite testing with different quantitative cutoffs. CK7 and CK20 were nonspecific. Ang classification had reasonable correlation with histologic subclassification of tubular cases as INT versus PB with high specificity but low sensitivity and ambiguous category was large (29%) and included also some classical cases. Prognostically, Ang classification approached but did not reach statistical significance, even when their large "ambiguous" group was eliminated and only tubular cases were analyzed (Ang-INT vs. Ang-PB; P=0.08). The Chang panel, in which the definition of the INT subcategory is not clearly defined, only marginally reached prognostic significance when tested as MUC1+/CDX2- versus MUC1-/CDX2+ and only by Wilcoxon test (P=0.0485) but 31% of the cases were "unclassifiable." The only individual marker that was found to have direct and strong correlation with the clinical outcome was MUC5AC (not used in the Ang or Chang panels), with statistically significant survival differences found with various cutoffs tested (for 20% cutoff, 5-y survival, 68% vs. 31%; P=0.0002). In addition, MUC5AC significantly stratified the histologically PB and INT cases (P=0.01 and 0.03, respectively), as well as Ang's ambiguous and Chang's unclassified cases (P=0.006 and 0.007, respectively). In conclusion, the widely used putative lineage markers, MUC1/MUC2/CK7/CK20/CDX2, do not seem to have direct/significant prognostic correlation either individually or in combination of Ang and Chang panels. Ang panel is helpful as an adjunct in determining the cell lineage with a few caveats. MUC5AC proves to be a significant independent prognosticator and should be incorporated into evaluation of ampullary carcinomas.
Asunto(s)
Adenocarcinoma/diagnóstico , Ampolla Hepatopancreática/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/diagnóstico , Mucina 5AC/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/patología , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias del Conducto Colédoco/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mucina 6/metabolismo , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: The HMGA2 protein has experimentally been linked to EMT and cancer stemness. Recent studies imply that tumour-stroma interactions regulate these features and thereby contribute to tumour aggressiveness. METHODS: We analysed 253 cases of pancreatic ductal adenocarcinoma (PDAC) and 155 cases of ampullary adenocarcinoma (AAC) for HMGA2 expression by IHC. The data were correlated with stroma abundance and supplemented by experimental studies. RESULTS: HMGA2 acts as an independent prognostic marker associated with a significantly shorter overall survival in both tumour types. Overall, HMGA2-positivity was more frequent in patients with PDAC than with AAC. The HMGA2 status in tumour cells significantly correlated with the abundance of PDGFRß-defined stroma cells. In vivo co-injection of Panc-1 cancer cells with pancreatic stellate cells increased tumour growth in a manner associated with increased HMGA2 expression. Furthermore, in vitro treatment of Panc-1 with conditioned media from PDGF-BB-activated stellate cells increased their ability to form tumour spheroids. CONCLUSIONS: This study identifies HMGA2 expression in tumour cells as an independent prognostic marker in PDAC and AAC. Correlative data analysis gives novel tissue-based evidence for a heterotypic cross-talk with stroma cells as a possible mechanism for HMGA2 induction, which is further supported by experimental models.
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Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias del Conducto Colédoco/metabolismo , Proteína HMGA2/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/patología , Anciano , Ampolla Hepatopancreática , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Neoplasias del Conducto Colédoco/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Trasplante de Neoplasias , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/metabolismo , Pronóstico , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células del Estroma/metabolismo , Tasa de SupervivenciaRESUMEN
Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n = 148) and ampullary (n = 76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p = 0.002), Gal-9 (p = 0.003), HVEM (p = 0.001), IDO (p = 0.049), HLA-G (p = 0.004) and high CD8/FoxP3 TIL ratio (p = 0.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p < 0.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials.
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Antígeno B7-H1/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Galanina/metabolismo , Antígenos HLA-G/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Pancreáticas/mortalidad , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/inmunología , Ampolla Hepatopancreática/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias del Conducto Colédoco/inmunología , Neoplasias del Conducto Colédoco/metabolismo , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Pronóstico , Estudios RetrospectivosAsunto(s)
Neoplasias del Conducto Colédoco/patología , Tumores de Células Gigantes/patología , Anciano , Conducto Colédoco/metabolismo , Conducto Colédoco/patología , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/metabolismo , Diagnóstico Diferencial , Femenino , Tumores de Células Gigantes/diagnóstico , Tumores de Células Gigantes/metabolismo , Histonas/genética , Humanos , MutaciónRESUMEN
Literature on non-ampullary-duodenal carcinomas is limited. We analyzed 47 resected non-ampullary-duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry (n=38) revealed commonness of 'gastro-pancreatobiliary markers' (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas 'intestinal markers' were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary-duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary (n=355) and pancreatic ductal (n=227) carcinomas, non-ampullary-duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs 1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary-duodenal carcinomas (59 and 52%; P=0.78), but was significantly better than the ampullary ductal (41 and 29%, P<0.001) and pancreatic (28 and 18%, P<0.001) carcinomas. In conclusion, non-ampullary-duodenal carcinomas are more histologically heterogeneous than previously appreciated. Their morphologic versatility (commonly showing gastro-pancreatobiliary lineage and hitherto unrecognized patterns), frequent plaque-like growth minus an adenoma component, and frequent expression of gastro-pancreatobiliary markers suggest that many non-ampullary-duodenal carcinomas may arise from Brunner glands or gastric metaplasia or heterotopic pancreatobiliary epithelium. The clinical behavior of non-ampullary-duodenal carcinoma is closer to that of ampullary-duodenal subset of ampullary carcinomas, but is significantly better than that of ampullary ductal and pancreatic cancers. The frequency of mismatch repair protein alterations suggest that routine testing should be considered, especially in the non-ampullary-duodenal carcinomas with plaque-like growth and pushing-border infiltration.