RESUMO
Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-ß), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-ß signaling using recombinant soluble human TGF-ß receptor type II and TGF-ß-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-ß from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Vírus da Necrose Pancreática Infecciosa/metabolismo , Proteínas/metabolismo , Western Blotting , Caderinas/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Ensaio de Unidades Formadoras de Colônias , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Mucoproteínas , Invasividade Neoplásica/fisiopatologia , Proteínas Oncogênicas , Prognóstico , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/farmacologia , Vimentina/metabolismoRESUMO
AIMS: Of the recognized precursor lesions of pancreatic adenocarcinoma, pancreatic intraepithelial neoplasia (PanIN) is the most common form. However, little is known about the relationship between the grade of PanIN and prognosis for patients with invasive ductal carcinoma. METHODS AND RESULTS: In 124 patients with invasive ductal carcinoma, we examined the grade and number of PanIN lesions in all slides of resected pancreas. The prevalence rates of PanIN-1A, PanIN-1B, PanIN-2 and PanIN-3 were 86%, 84%, 57% and 30%, respectively. We allocated PanIN-2 and PanIN-3 cases into a PanIN-high group, and cases showing PanIN-1A, PanIN-1B or absence of PanIN into a PanIN-low group. In clinicopathological analysis, PanIN-high status was significantly correlated with the number of PanIN lesions (P < 0.0001). Disease-free and overall survival were statistically better in the PanIN-high group than in the PanIN-low group (P = 0.0005 and P = 0.0003). Univariate and multivariate analyses revealed that tumour size and PanIN-low status were statistically significant factors for a poorer prognosis (P = 0.042 and P = 0.007). CONCLUSIONS: In a pathological examination, it is important to evaluate the grade and number of PanINs in assessing the prognosis of pancreatic cancer.
Assuntos
Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Idoso , Atrofia , Carcinoma Ductal Pancreático/secundário , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , PrognósticoRESUMO
BACKGROUND: Interactions between cancer cells and surrounding cancer-associated fibroblasts (CAFs) play an important role in cancer progression. Invasive ductal carcinoma (IDC) of the pancreas is characterized by abundant fibrous connective tissue called desmoplasia. Podoplanin (PDPN) is a lymphatic vessel marker (D2-40), and expression of PDPN by stromal CAFs has been reported to be a prognostic indicator in various types of cancer. METHODS: Expression of PDPN in pancreatic IDCs was assessed by immunohistochemical examination in 105 patients who underwent pancreatic resection. Primary CAFs were established from pancreatic cancer tissue obtained by surgery. Quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis were performed to investigate PDPN expression in CAFs. We sorted CAFs according to PDPN expression, and analyzed the functional differences between PDPN+ CAFs and PDPN- CAFs using indirect co-culture with pancreatic cancer cell lines. We also investigated the culture conditions to regulate PDPN expression in CAFs. RESULTS: PDPN expression in stromal fibroblasts was associated with lymphatic vessel invasion (P = 0.0461), vascular invasion (P = 0.0101), tumor size ≥ 3 cm (P = 0.0038), histological grade (P = 0.0344), Union for International Cancer Control classification T stage (P = 0.029), and shorter survival time (P < 0.0001). Primary CAFs showed heterogeneous PDPN expression in vitro. Moreover, migration and invasion of pancreatic cancer cell lines (PANC-1 and SUIT-2) were associated with PDPN expression in CAFs (P < 0.01) and expression of CD10, matrix metalloproteinase (MMP) 2, and MMP3. In cultured CAFs, PDPN positivity changed over time under several conditions including co-culture with cancer cells, different culture media, and addition of growth factor. CONCLUSIONS: PDPN-expressing CAFs enhance the progression of pancreatic IDC, and a high ratio of PDPN-expressing CAFs is an independent predictor of poor outcome. Understanding the regulation of the tumor microenvironment is an important step towards developing new therapeutic strategies.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Fibroblastos/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Técnicas de Cocultura , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: Pancreatic cancer (PC), a hypovascular tumor, thrives under hypoxic conditions. Pancreatic stellate cells (PSCs) promote PC progression by secreting soluble factors, but their functions in hypoxia are poorly understood. This study aimed to clarify the effects of hypoxic conditions on the interaction between PC cells and PSCs. METHODS: We isolated human PSCs from fresh pancreatic ductal adenocarcinomas and analyzed functional differences in PSCs between normoxia (21% O2) and hypoxia (1% O2), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule-connective tissue growth factor (CTGF)-in PSCs under hypoxic conditions, using RNA interference techniques. RESULTS: Conditioned media from hypoxic PSCs enhanced PC cell invasiveness more intensely than that from normoxic PSCs (P < 0.01). When co-cultured with PSCs, PC cell invasion was more enhanced under hypoxia than under normoxia (P < 0.05). Among various soluble factors, which were related to invasiveness, CTGF was one of the overexpressed molecules in hypoxic PSCs. A higher level of CTGF expression was also found in supernatant of hypoxic PSCs than in supernatant of normoxic PSCs. PC cell invasiveness was reduced by CTGF knockdown in hypoxic PSCs co-cultured with PC cells (P < 0.05). CONCLUSION: Hypoxia induces PSCs' secretion of CTGF, leading to enhancement of PC invasiveness. CTGF derived from hypoxia-stimulated PSCs may be a new therapeutic target for pancreatic cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Comunicação Celular/fisiologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hipóxia/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Western Blotting , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Chronic ischemic enteritis can cause intestinal strictures, but extensive resection of the small intestine may leave patients with short bowel syndrome. Thus, the importance of preserving diseased small bowel is now recognized. We report a case of successful side-to-side isoperistaltic strictureplasty (SSIS), performed to prevent short bowel syndrome, in a patient with ischemic enteritis caused by strangulated intestinal obstruction. SSIS is useful for preserving the intestinal absorptive function in patients with a long narrowed bowel loop caused by ischemic change. To our knowledge, this is the first report of the successful treatment of a long stricture resulting from ischemic enteritis, achieved by performing SSIS.
Assuntos
Enterite/cirurgia , Obstrução Intestinal/cirurgia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/cirurgia , Isquemia/cirurgia , Idoso , Anastomose em-Y de Roux , Doença Crônica , Meios de Contraste , Fluoroscopia , Humanos , Masculino , Síndrome do Intestino Curto/prevenção & controleRESUMO
Background: Plasmalogens have been shown to improve neurodegenerative pathology and cognitive function. We hypothesized that plasmalogens work in small amounts as a kind of hormone interacting with a G protein-coupled receptor, and then explored the effects of scallop-derived purified plasmalogens on psychobehavioral conditions in a randomized placebo-controlled trial of college athletes in Japan. Methods and materials: Eligible participants were male students aged 18-22 years who belonged to university athletic clubs. They were randomly allocated to either plasmalogen (2 mg per day) or placebo treatment of 4 weeks' duration. The primary outcome was the T-score of the Profile of Mood States (POMS) 2-Adult Short, and the secondary outcomes included the seven individual scales of the POMS 2, other psychobehavioral measures, physical performance, and laboratory measurements. The trial was registered at the Japan Registry of Clinical Trials (jRCTs071190028). Results: Forty participants (20 in the plasmalogen group and 20 in the placebo group) completed the 4-week treatment. The Total Mood Disturbance (TMD) score of the plasmalogen group showed a greater decrease at 4 weeks than that of the placebo group while the between-group difference was marginally significant (p = 0.07). The anger-hostility and fatigue-inertia scores of the POMS 2 decreased significantly in the plasmalogen group, but not in the placebo group, at 4 weeks. Between-group differences in those scores were highly significant (p = 0.003 for anger-hostility and p = 0.005 for fatigue-inertia). The plasmalogen group showed a slight decrease in the Athens Insomnia Scale at 2 weeks, and the between-group difference was near-significant (p = 0.07). The elapsed time in minute patterns on the Uchida-Kraepelin test, which is a marker of mental concentration, revealed significantly greater performance in the plasmalogen group than in the placebo group. There were no between-group differences in physical and laboratory measurements. Conclusion: It is suggested that orally administered plasmalogens alleviate negative mood states and sleep problems, and also enhance mental concentration.
RESUMO
Imaging of a 53-year-old Japanese man revealed two tumors in the liver and a tumor in the head of the pancreas with a swelling lymph node. A needle biopsy for the liver tumors was performed, revealing a neuroendocrine tumor. Enucleation, lymphadenectomy, and partial hepatectomy were performed. The microscopic examination identified many tumor cells with intracytoplasmic inclusions arranged in a nested, cord, or tubular fashion. The intracytoplasmic inclusions displayed densely eosinophilic globules and displaced the nuclei toward the periphery, which constitutes "rhabdoid" features. The tumor cells were positive for synaptophysin and weakly positive for NCAM, but negative for chromogranin A. Epithelial markers (AE1/AE3 and CAM5.2) accentuated intracytoplasmic globules. Pancreatic neuroendocrine tumors with rhabdoid features are very rare. Generally, rhabdoid features are aggressive and dedifferentiated characteristics of various types of tumor. Pancreatic neuroendocrine tumors containing rhabdoid cells tend to display extrapancreatic spread at the time of presentation, although some of these tumors with rhabdoid features are not always associated with aggressive behavior.
Assuntos
Neoplasias Hepáticas/secundário , Tumores Neuroendócrinos/secundário , Neoplasias Pancreáticas/patologia , Tumor Rabdoide/secundário , Biomarcadores Tumorais/análise , Biópsia por Agulha , Endossonografia , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/química , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/química , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/cirurgia , Tumor Rabdoide/química , Tumor Rabdoide/cirurgia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The aim of this study was to investigate preoperative factors associated with ductal carcinoma in situ (DCIS) upstaged to invasive ductal carcinoma (IDC) and sentinel lymph node (SLN) status in patients who underwent mastectomy for a preoperative diagnosis of DCIS. METHODS: The medical records of 220 patients who underwent mastectomy for a preoperative diagnosis of DCIS were retrospectively reviewed. RESULTS: Fifty-one (22.6%) of 226 lesions were upgraded to IDC after mastectomy. Preoperative factors associated with upstaging to IDC included patient-reported signs and symptoms, a clinically palpable mass, ultrasound findings classified as category 4 or 5, the ultrasound appearance of a mass or widely distributed non-mass abnormality (NMA), and a high Ki67 index. The prevalence of SLN macrometastasis was 0.9%. IDC was diagnosed for 10.9% of lesions of a preoperative ultrasound category of 0-3, 13.0% of those with no mass or NMA detected by ultrasonography, and 14.1% of lesions preoperatively diagnosed by methods other than core needle biopsy (CNB). Of those lesions, none was associated with SLN metastasis. CONCLUSIONS: Routinely performing SLN biopsy for patients undergoing mastectomy for a preoperative diagnosis of DCIS is overtreatment, because the prevalence of SLN metastasis was low. SLN biopsy can be omitted for most patients. In particular, we suggest omitting SLN biopsy for patients who have lesions of ultrasound category 0-3, who have neither a mass nor NMA detected by ultrasound, or whose initial diagnosis was made based on a specimen obtained by methods other than CNB.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Mastectomia , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/cirurgia , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased 18F-fluorodeoxyglucose (18F-FDG) uptake. We examined SLC2A1/GLUT1 expression in the mural nodules of 180 IPMN specimens to distinguish malignant/benign tumors. A mural nodule was detected in 80 (44.4%) of the IPMNs, and was detected in 18.6% (13/70) of the IPMN-low (dysplasia) specimens, 36.1% (13/36) of the IPMN-int, 93.3% (28/30) of the IPMN-high, and 59.1% (26/44) of the IPMN-inv (with an associated invasive carcinoma) specimens. The sensitivity for detecting mural nodules was 81.7% by endoscopic ultrasonography, 70% by contrast-enhanced computed tomography and 54% by endoscopic retrograde cholangiopancreatography. SLC2A1/GLUT1 expression in the mural nodules was recognized in the basal and basolateral cytomembrane of tumor cells and was expressed in 15.4% (2/13) of the IPMN-low, 15.4% (2/13) of the IPMN-int, 71.4% (20/28) of the IPMN-high and 84.6% (22/26) of the IPMN-inv groups. The SLC2A1/GLUT1 expression was significantly higher in the IPMN-high and IPMN-inv mural nodules than in those of the IPMN-low and IPMN-int groups. Our findings suggest that SLC2A1/GLUT1 is expressed late in the adenoma-carcinoma sequence during carcinogenesis in IPMN, and SLC2A1/GLUT1 act as therapeutic target for malignant IPMN.
Assuntos
Biomarcadores Tumorais/análise , Transportador de Glucose Tipo 1/análise , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Pancreáticas/química , Idoso , Biópsia , Colangiopancreatografia Retrógrada Endoscópica , Endossonografia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/diagnóstico por imagem , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
A 71-year-old woman, previously treated for malignant lymphoma, was admitted to our hospital with a tumor in the right breast. The tumor size was 2.0 cm in diameter, and the borderline was unclear. The core needle biopsy material revealed an invasive adenocarcinoma with metaplastic change. Right mastectomy and sentinel lymph node biopsy was performed. Histologically, the tumor was composed of mucus-secreting, epidermoid, and intermediate cells. These findings confirmed the diagnosis as mucoepidermoid carcinoma (MEC) of the breast. MEC is more frequently observed in the salivary glands and occurs rarely in the breast, with an incidence of approximately 0.3% of all breast cancers. Because of the rarity of the disease, the clinicopathological features and clinical outcome have not been fully investigated. The relationship between MEC of the breast and lymphoma are unclear. Here we report a rare case of MEC of the breast.
RESUMO
The present study aimed to investigate the prognostic usefulness of the expression of glucose transporter type 1 (GLUT-1) and GLUT-2, hypoxia-inducible factor 1α (HIF-1α) and insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) in pancreatic neuroendocrine tumors (pNETs). Immunohistochemical staining for GLUT-1, GLUT-2, HIF-1α and IMP3 was performed in 70 pNET specimens. The expression of GLUT-1 and HIF-1α was significantly higher in the World Health Organization grade 2 (G2), neuroendocrine carcinoma cases and mixed-type pNETs compared with the G1 cases. Vessel invasion, a high Ki-67 labeling index and a high mitotic count were significantly more frequent in the GLUT-1- and HIF-1α-positive cases compared with the negative cases. Lymph node metastasis was significantly higher in the GLUT-1-positive cases than in the negative cases. Insulin expression was significantly higher in the IMP3-positive cases than the negative cases. The GLUT-1 expression group experienced a significantly poor disease-free survival rate compared with the negative GLUT-1 expression group. HIF-1α expression was significantly correlated with poor disease-free survival and overall survival rates. A multivariate analysis revealed that lymph node metastasis was an independent risk factor for disease-free survival in all cases. In the G1/G2 group, tumor size and lymph node metastasis were independent risk factors for disease-free survival. Overall, the results suggested that GLUT-1 is a useful prognostic biomarker for pNETs.
RESUMO
OBJECTIVES: Glucagon-like peptide 1 (GLP-1) interacts with its specific high-affinity receptor, glucagon-like peptide 1 receptor (GLP-1R), and induces cellular growth and inhibition of apoptosis in pancreatic ß cells. The aim of this study was to investigate the significance of GLP-1R expression in pancreatic neuroendocrine tumors (PNETs). METHODS: Glucagon-like peptide 1 receptor expression was semiquantitatively evaluated by immunohistochemical staining in 50 resected PNETs, and the correlation between the GLP-1R expression and clinicopathologic features was investigated. RESULTS: There were 23 PNETs with positive expression and 27 PNETs with negative expression of GLP-1R. Positive expression of GLP-1R was more frequently observed in insulinoma than in gastrinoma and nonfunctioning tumor (P < 0.05). Although expression status of GLP-1R did not affect the prognosis of the patients with PNETs (P = 0.82), most of the metastatic sites such as lymph node and liver showed positive staining for GLP-1R (8 of 11 PNETs, 73%). CONCLUSIONS: Glucagon-like peptide 1 receptor would be a diagnostic marker of insulinoma and might become a molecular target for treatment of metastatic PNETs and hormonal regulation of insulin.
Assuntos
Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Glucagon/biossíntese , Adulto , Idoso , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: It is difficult to predict the malignant potential of pancreatic neuroendocrine tumors (PNETs) precisely. This study investigated the validity of a new grading system adopted by the World Health Organization 2010 classification to determine risk factors for recurrence of PNETs. METHODS: Data of 70 patients with PNETs who underwent curative resection were retrospectively examined by uni- and multivariate analyses. Histopathological findings were re-reviewed by experienced pathologists. NET G1 was defined as mitotic count <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index, and NET G2 as 2-20 mitosis per 10 HPF and/or 3-20% Ki67 index. RESULTS: There were 58 patients with NET G1 and 12 with NET G2. Incidence of recurrence was 11.4%. Univariate analysis demonstrated significant risk factors for recurrence including NET G2 of histological grade (P = 0.0089), male gender (P = 0.0333), tumor size ≥ 20 mm (P = 0.0117), lymph node metastasis (P = 0.0004), liver metastasis (P < 0.0001), lymphatic invasion (P = 0.046), and neural invasion (P = 0.0002). By multivariate analysis, histological grade (hazard ratio; 59.76, P = 0.0022) and neural invasion (hazard ratio; 147.49, P = 0.0016) were significantly associated with recurrence of PNETs. CONCLUSIONS: This study confirmed the prognostic relevance of the new grading classification and that evaluation of perineural invasion and histological grade should be considered as prognostic predictors in well-differentiated PNETs (NET G1 and G2).
Assuntos
Gradação de Tumores/classificação , Recidiva Local de Neoplasia/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Análise de Variância , Estudos de Coortes , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Organização Mundial da Saúde , Adulto JovemRESUMO
A thickened, enhanced cyst wall on imaging examinations is one of the "worrisome features" described in the consensus guidelines for management of intraductal papillary mucinous neoplasm of the pancreas (IPMN). Podoplanin (PDPN) expression by cancer-associated fibroblasts is known to be an indicator of poor prognosis in some types of cancer. We performed immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in IPMN lesions and determined the pathological wall thickness by measuring the thinnest and thickest α-SMA-positive parts of the wall of the largest cyst in each case, and the mean of these two values was recorded as the wall thickness. The thickness of the pathological wall increased with progression from IPMN with low-grade dysplasia to IPMN with an invasive carcinoma. The pathological wall was thicker in IPMN with main duct involvement, nongastric-type IPMN, and IPMN with mural nodules. We also stained for PDPN and assessed the thickness of cyst wall staining as for α-SMA. The thickness of the PDPN-positive cyst wall varied in a pattern similar to the thickness of the α-SMA-positive pathological cyst wall. PDPN-positive stromal fibroblasts in the invasive component of IPMN-IC were evaluated as a ratio to α-SMA-positive fibroblasts. A high ratio (>50 %) of PDPN-positive stromal fibroblasts was a predictor of poor outcome. PDPN expression in the cyst wall correlates with the progression of IPMN. PDPN may be a significant prognostic marker of IPMN-IC.
Assuntos
Adenocarcinoma Mucinoso/patologia , Carcinoma Ductal Pancreático/patologia , Glicoproteínas de Membrana/análise , Neoplasias Pancreáticas/patologia , Actinas/análise , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/mortalidade , Fator de Crescimento Transformador beta1/análiseRESUMO
Intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanINs) are important premalignant lesions of pancreatic cancer. Ezrin is a member of the ezrin, radixin, and moesin protein family and acts as a cross-linker between the plasma membrane and the actin cytoskeleton. We investigated the roles of ezrin during carcinogenesis in IPMN and invasive ductal carcinoma and examined whether ezrin was a prognostic factor. We examined ezrin and phosphorylated ezrin (p-ezrin) expression in 131 IPMNs, 47 PanINs, and 59 invasive ductal carcinomas by immunohistochemical staining. Ezrin and p-ezrin (tyr354) expressions were significantly higher in IPMN with an associated invasive carcinoma, compared with those in IPMN with high-grade dysplasia (P = .03 and P = .0007, respectively). In all grades of PanINs, ezrin and p-ezrin (tyr353) were highly expressed. In patients with invasive ductal carcinoma, the presence of PanIN-2 or PanIN-3 was significantly correlated with positive ezrin and p-ezrin (tyr353) expression of the invasive ductal carcinoma component (P = .01 and P = .0004). The negative p-ezrin (tyr353) expression group of invasive ductal carcinoma showed a significantly worse prognosis than did the positive p-ezrin (tyr353) expression group by survival analysis (P = .04) and was a statistically significant adverse prognostic factor by both univariate and multivariate analyses (P = .048 and P = .015). Ezrin phosphorylation sites differ between the developments of IPMN and PanIN. Although p-ezrin (tyr354) expression in IPMNs is associated with tumor invasion, p-ezrin (tyr353) expression in invasive ductal carcinoma plays an important role not in tumor invasion and metastasis but in the early development of PanINs.
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Adenocarcinoma Mucinoso/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Papilar/metabolismo , Proteínas do Citoesqueleto/biossíntese , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/análise , Carcinoma in Situ/mortalidade , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/mortalidade , Carcinoma Papilar/patologia , Proteínas do Citoesqueleto/análise , Progressão da Doença , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , FosforilaçãoRESUMO
Recently, various studies have shown that insulin-like growth factor II messenger RNA-binding protein-3 (IMP3) is a useful diagnostic marker for malignant lesions and a prognostic marker for poor survival in several kinds of tumors. However, the value of IMP3 as a diagnostic and prognostic marker in intraductal papillary mucinous neoplasm (IPMN) of pancreas has been unclear until now. In this study, we examined IMP3 immunohistochemical expression in 190 resection samples and 15 biopsy samples of IPMN and analyzed the value of IMP3 as a diagnostic and prognostic marker. IMP3 expression was recognized in 71.8% (28/39) of IPMNs with high-grade dysplasia and in 81.3% (26/32) of IPMNs with an associated invasive carcinoma (IPMN-IC), but it was not found in any IPMNs with low-grade dysplasia or in IPMNs with intermediate dysplasia. IMP3 expression was significantly higher in cancerous lesions (IPMN with high-grade dysplasia and IPMN-IC) than in noncancerous lesions (IPMN with low-grade dysplasia and IPMN with intermediate-grade dysplasia), with a sensitivity of 76.1% and a specificity of 100% (P < .001). We also identified a significant difference in IMP3 expression between cancerous lesions and noncancerous lesions in biopsy specimens (P = .027). In IPMN-IC, disease-specific survival was significantly shorter in the high-expression group (>50% tumor staining) than in the low-expression group (≤50% tumor staining; P = .0069). In conclusion, our findings show that IMP3 is a useful diagnostic marker for distinguishing between noncancerous and cancerous lesions and is a valuable prognostic biomarker in IPMN.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Papilar/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Proteínas de Ligação a RNA/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Papilar/metabolismo , Carcinoma Papilar/mortalidade , Feminino , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/metabolismo , Taxa de SobrevidaRESUMO
Biliary diverticulum or type II congenital biliary dilation accounts for only 1-2% of all patients with congenital biliary dilation. The association between pancreaticobiliary maljunction (PBM) and this type of anomaly remains unclear. A 40-year-old Japanese woman presented with a history of repeated upper abdominal pain for more than 30 years. Computed tomography showed a cystic lesion (diameter 30 mm) arising from the common bile duct. Magnetic resonance cholangiopancreatography revealed a biliary diverticulum (diameter 33 mm) and the cystic duct entering the diverticulum. There was no dilation of the intrahepatic or extrahepatic ducts. Endoscopic retrograde cholangiopancreatography demonstrated PBM. A diagnosis of type II biliary diverticulum with PBM was made, and the patient underwent laparoscopic resection of the diverticulum combined with cholecystectomy. Pathological examination of the resected specimen showed slight inflammation, but no malignancy in the diverticulum or gallbladder. The patient's postoperative course was uneventful. To our knowledge, this is the first report of successful laparoscopic resection of biliary diverticulum associated with pancreaticobiliary maljunction.
RESUMO
BACKGROUND: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production. METHODS: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated. RESULTS: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm. CONCLUSIONS: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.