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INTRODUCTION: A risk prediction test was previously validated to predict progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). The aim of our study was to independently validate this test to predict the risk of progression to HGD/EAC in BE patients with nondysplastic (ND), indefinite for dysplasia and low-grade dysplasia (LGD). METHODS: A single-blinded, case-control study was conducted to stratify patients with BE as low, intermediate, or high risk for progression to HGD/EAC within 5 years using a previously described risk prediction test. Patients with BE who progressed to HGD/EAC after at least 1 year (n = 58) were matched to patients undergoing surveillance without progression (n = 210, median surveillance 7 years). Baseline biopsies with subspecialist diagnoses of ND, indefinite for dysplasia, or LGD were tested in a blinded manner, and the predictive performance of the test was assessed. RESULTS: This risk prediction test stratified patients with BE based on progression risk with the high-risk group at 4.7-fold increased risk for HGD/EAC compared with the low-risk group (95% confidence interval 2.5-8.8, P < 0.0001). Prevalence-adjusted positive predictive value at 5 years was 23%. The high-risk class and male sex provided predictive power that was independent of pathologic diagnosis, age, segment length, and hiatal hernia. Patients with ND BE who scored high risk progressed at a higher rate (26%) than patients with subspecialist-confirmed LGD (21.8%) at 5 years. DISCUSSION: A risk prediction test identifies patients with ND BE who are at high risk for progression to HGD/EAC and may benefit from early endoscopic therapy or increased surveillance.
Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/epidemiologia , Esôfago/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Esôfago de Barrett/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Esôfago/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Processamento de Imagem Assistida por Computador , Queratina-20/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Racemases e Epimerases/metabolismo , Receptor ErbB-2/metabolismo , Medição de Risco , Proteína Supressora de Tumor p53/metabolismo , Conduta ExpectanteRESUMO
AIMS: Abnormal p53 protein expression detected by immunohistochemistry (IHC) in Barrett's oesophagus (BO) is reported to be a prognostic biomarker for progression to high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC). We evaluated our use of p53 IHC for patients with BO under surveillance from 2010 to 2016 in a single academic institution. METHODS AND RESULTS: We identified 78 patients under surveillance for BO who had biopsies evaluated for abnormal p53 expression in conjunction with routine histology and 892 patients who had histological evaluation alone. All available p53 IHC slides were rescored as wild-type or abnormal. We evaluated the risk of subsequent diagnosis with HGD and OAC. p53-tested patients were significantly more likely to be diagnosed with indefinite dysplasia (IND) or low-grade dysplasia (LGD), compared to patients who were not tested (79.5 versus 10.8%, P = 7.4 × 10-40 ). Almost half (46.9%) of patients with abnormal p53 expression were diagnosed with HGD or OAC within 5 years, compared to 5.9% with wild-type p53, and 7.6% of patients not tested (P = 2.6 × 10-18 ). However, this difference was heavily influenced by other risk factors, including dysplasia grade, in multivariate analyses. In the subgroup of patients diagnosed with IND (n = 109), abnormal p53 expression was associated with a fourfold increase (1.2-13.3, P = 0.023) in risk of HGD/OAC relative to untested patients diagnosed with IND, independent of other risk factors. CONCLUSION: In patients under surveillance for BO in a single academic institution, we found evidence that selective use of p53 IHC in conjunction with routine histology modestly improved risk stratification by identifying patients with IND at higher risk of a subsequent diagnosis of HGD or OAC.
Assuntos
Esôfago de Barrett/patologia , Biomarcadores Tumorais/análise , Lesões Pré-Cancerosas/patologia , Proteína Supressora de Tumor p53/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/genética , Biomarcadores Tumorais/genética , Mucosa Esofágica/patologia , Neoplasias Esofágicas/patologia , Lesões Pré-Cancerosas/genética , Hidrolases Anidrido Ácido/genética , Adulto , Idoso , Esôfago de Barrett/patologia , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Variações do Número de Cópias de DNA , Progressão da Doença , Éxons/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/patologia , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND & AIMS: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress. METHODS: We performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors. RESULTS: TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy). CONCLUSIONS: In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.
Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Lesões Pré-Cancerosas/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/patologia , Biópsia , Estudos de Casos e Controles , Progressão da Doença , Neoplasias Esofágicas/patologia , Esofagoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Lesões Pré-Cancerosas/patologia , Prognóstico , Estudos RetrospectivosRESUMO
Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and nonsurgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Instabilidade Cromossômica , Cromossomos Humanos Par 17/genética , Neoplasias Esofágicas/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Idoso , Variações do Número de Cópias de DNA , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND AND AIMS: The diagnosis of low-grade dysplasia (LGD) in Barrett's esophagus (BE) is subject to substantial interobserver variation. Our central aim in this study is to compare independent pathology practices using objective measures of BE risk stratification proficiency, including frequency of diagnosis and rate of progression, with high-grade dysplasia (HGD) or adenocarcinoma (EAC) after the first diagnosis of LGD. METHODS: We retrospectively evaluated over 29,000 endoscopic biopsy cases to identify 4734 patients under endoscopic biopsy surveillance for BE in a healthcare system with multiple independent pathology practices: a subspecialized GI pathology group (SSGI; 162 BE cases per pathologist annually), 3 high BE volume general surgical pathology practices (GSPs; >50 BE cases per pathologist annually), and multiple low BE volume GSPs (10.6 BE cases per pathologist annually). We measured LGD diagnosis frequencies and rates of diagnostic progression to HGD or EAC in patients diagnosed with LGD. RESULTS: The proportion of all BE cases diagnosed as LGD (LGD/BE diagnosis ratio) ranged from 1.1% to 6.8% in the different hospital settings (P < .001). The cumulative proportion of patients with HGD or EAC within 2 years of the first diagnosis of LGD was 35.3% in the SSGI and ranged from 1.4% to 14.3% in the GSPs (P < .001). LGD diagnosed by the GSP with the lowest LGD/BE diagnosis ratio had an adjusted risk of progression similar to LGD diagnosed by subspecialists (hazard ratio, .42; 95% CI, .06-3.03). However, when LGD was diagnosed by other generalists, the adjusted risk of progression was 79% to 91% lower than subspecialists (P < .001). When LGD was diagnosed in a low-volume GSP practice, the risk of progression was not significantly increased relative to patients with nondysplastic BE (hazard ratio, 1.3; 95% CI, .4-3.9). CONCLUSIONS: General surgical pathologists and subspecialists show highly significant differences with respect to LGD/BE ratio, risk of progression relative to nondysplastic BE, crude annual progression rates, and the cumulative 2-year progression rate after LGD. These metrics can be used to assess proficiency in BE risk stratification in historical cases. Some general practitioners were able to achieve results similar to subspecialists. General surgical pathologists with little annual experience evaluating BE biopsy specimens did not successfully risk stratify patients with BE.
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Esôfago de Barrett/patologia , Progressão da Doença , Neoplasias Esofágicas/patologia , Patologia/normas , Lesões Pré-Cancerosas/patologia , Idoso , Esôfago de Barrett/fisiopatologia , Esôfago de Barrett/cirurgia , Biópsia por Agulha , Neoplasias Esofágicas/fisiopatologia , Neoplasias Esofágicas/cirurgia , Esofagoscopia/métodos , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Patologia/tendências , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Estatísticas não ParamétricasRESUMO
BACKGROUND & AIMS: It is important to identify superficial (T1) gastroesophageal adenocarcinomas (EAC) that are most or least likely to metastasize to lymph nodes, to select appropriate therapy. We aimed to develop a risk stratification model for metastasis of superficial EAC to lymph nodes using pathologic features of the primary tumor. METHODS: We collected pathology data from 210 patients with T1 EAC who underwent esophagectomy from 1996 through 2012 on factors associated with metastasis to lymph nodes (tumor size, grade, angiolymphatic invasion, and submucosal invasion). Using these variables, we developed a multivariable logistic model to generate 4 categories for estimated risk of metastasis (<5% risk, 5%-10% risk, 15%-20% risk, or >20% risk). The model was validated in a separate cohort of 39 patients who underwent endoscopic resection of superficial EAC and subsequent esophagectomy, with node stage analysis. RESULTS: We developed a model based on 4 pathologic factors that determined risk of metastasis to range from 2.9% to 60% for patients in the first cohort. In the endoscopic resection validation cohort, higher risk scores were associated with increased detection of lymph node metastases at esophagectomy (P = .021). Among patients in the first cohort who did not have lymph node metastases detected before surgery (cN0), those with high risk scores (>20% risk) had 11-fold greater odds for having lymph node metastases at esophagectomy compared with patients with low risk scores (95% confidence interval, 2.3-52 fold). Increasing risk scores were associated with reduced patient survival time (P < .001) and shorter time to tumor recurrence (P < .001). Patients without lymph node metastases (pT1N0) but high risk scores had reduced times of survival (P < .001) and time to tumor recurrence (P = .001) after esophagectomy than patients with pT1N0 tumors and lower risk scores. CONCLUSIONS: Pathologic features of primary superficial EACs can be used, along with the conventional node staging system, to identify patients at low risk for metastasis, who can undergo endoscopic resection, or at high risk, who may benefit from induction or adjuvant therapy.
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Adenocarcinoma/patologia , Adenocarcinoma/secundário , Técnicas de Apoio para a Decisão , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/secundário , Linfonodos/patologia , Patologia/métodos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Modelos Estatísticos , Metástase Neoplásica , Medição de RiscoRESUMO
Distinction between multiple primary cancers and intrapulmonary metastases in patients with synchronous multifocal lung cancer can be challenging. Histological and genotypic assessment of multifocal lung tumors have been suggested to influence the staging. The aim of this study was to determine the role of morphology and genotype in staging of surgically treated multifocal non-small cell lung carcinoma. Synchronous lung cancers from 60 patients (42 with adenocarcinoma and 18 with squamous cell carcinoma), clinically considered to represent intrapulmonary metastases, were histologically subtyped according to the 2015 World Health Organization classification of lung tumors and subjected to genotypic analysis (KRAS, EGFR, BRAF, PIK3CA, ALK, MET and ROS1 in adenocarcinoma and PIK3CA and p16 in squamous cell carcinoma). Concordance between clinical criteria and histological subtyping was identified in about 50% of cases (P<0.0001). Genotypically, 44% of adenocarcinomas and 60% of squamous cell carcinomas with identified molecular alterations were considered to be intrapulmonary metastases. Concordance between histological and molecular staging was observed in 89% of adenocarcinomas and 56% of squamous cell carcinomas. Univariate survival analyses failed to demonstrate significant differences in overall or cancer-specific survival in patients with adenocarcinoma and squamous cell carcinomas restaged according to histology and/or molecular profile. Lymph node metastases (N1/N2 vs N0) (P=0.03) and age >65 years (P=0.05) were associated with shorter overall survival. In addition, squamous cell carcinomas with p16 deletion showed shorter overall survival when compared with squamous cell carcinomas without p16 deletion (P=0.05). No correlation between other molecular alterations, clinico-pathological characteristics and prognosis was found. Our study demonstrates that a comprehensive genotypic and morphological assessment of surgically treated multifocal lung cancers is feasible but not sufficient to establish their clonal relationship and prognosis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Esophageal adenocarcinoma (EAC) is associated with a dismal prognosis. The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy. The authors present results from the development of a serum-based, 4-protein (biglycan, myeloperoxidase, annexin-A6, and protein S100-A9) biomarker panel for EAC. METHODS: A vertically integrated, proteomics-based biomarker discovery approach was used to identify candidate serum biomarkers for the detection of EAC. Liquid chromatography-tandem mass spectrometry analysis was performed on formalin-fixed, paraffin-embedded tissue samples that were collected from across the Barrett esophagus (BE)-EAC disease spectrum. The mass spectrometry-based spectral count data were used to guide the selection of candidate serum biomarkers. Then, the serum enzyme-linked immunosorbent assay data were validated in an independent cohort and were used to develop a multiparametric risk-assessment model to predict the presence of disease. RESULTS: With a minimum threshold of 10 spectral counts, 351 proteins were identified as differentially abundant along the spectrum of Barrett esophagus, high-grade dysplasia, and EAC (P<.05). Eleven proteins from this data set were then tested using enzyme-linked immunosorbent assays in serum samples, of which 5 proteins were significantly elevated in abundance among patients who had EAC compared with normal controls, which mirrored trends across the disease spectrum present in the tissue data. By using serum data, a Bayesian rule-learning predictive model with 4 biomarkers was developed to accurately classify disease class; the cross-validation results for the merged data set yielded accuracy of 87% and an area under the receiver operating characteristic curve of 93%. CONCLUSIONS: Serum biomarkers hold significant promise for the early, noninvasive detection of EAC.
Assuntos
Adenocarcinoma/diagnóstico , Anexina A6/sangue , Biglicano/sangue , Biomarcadores Tumorais/sangue , Calgranulina B/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Esofágicas/diagnóstico , Peroxidase/sangue , Adenocarcinoma/sangue , Esôfago de Barrett/sangue , Cromatografia Líquida , Neoplasias Esofágicas/sangue , Humanos , Modelos Biológicos , Espectrometria de Massas em TandemRESUMO
The term pediatric autoimmune enteropathy was originally applied to a form of intractable diarrhea seen in children under the age of 6 months and characterized by male predominance, concurrent autoimmune-associated disorders, circulating gut autoantibodies, a lack of severe immunodeficiency and small bowel atrophy with prominent crypt apoptosis. However, recent studies have cast doubt over the specific clinicopathologic findings associated with this entity. We, therefore, collected 178 gastrointestinal biopsies from 14 patients and examined their clinical, serologic and pathologic findings. Patients at presentation ranged in age from birth to 15.9 years (median, 5.5 months; mean, 4.1 years) and included six males and eight females. All children suffered from chronic watery diarrhea and malnutrition. Concomitant-associated disorders were noted in 11 (79%) cases and included 10 (71%) with an immunodeficiency disorder and/or another autoimmune-related disease. Eleven patients (79%) were positive for anti-enterocyte antibodies. The salient findings of autoimmune enteropathy were most prominent in the small intestines and the majority (79%) of patients demonstrated villous blunting, crypt hyperplasia, mononuclear cell inflammatory expansion of the lamina propria and crypt apoptosis. The remaining (21%) patients showed marked intraepithelial lymphocytosis reminiscent of celiac disease. Further, acute cryptitis and crypt abscesses were seen in seven (50%) patients obscuring the presence of apoptosis. The absence of Paneth cells, goblet cells or both was noted in seven (50%) patients. Follow-up information was available for all patients with 13 (93%) receiving immunosuppressant therapy and demonstrating partial-to-complete response. In total, three patients died from continued diarrhea and sepsis with one decedent before treatment could be initiated. In summary, autoimmune enteropathy in children is a heterogenous disease with protean clinical and pathologic findings. Although anti-enterocyte antibodies were identified in the majority of the cases, their presence was variable and insensitive. In addition, pediatric autoimmune enteropathy was frequently encountered in the setting of immunodeficiency disorders.
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Autoanticorpos/análise , Autoimunidade , Trato Gastrointestinal/imunologia , Síndromes de Imunodeficiência/imunologia , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Autoimunidade/efeitos dos fármacos , Biópsia , Criança , Pré-Escolar , Diarreia/imunologia , Enterócitos/imunologia , Enterócitos/patologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Masculino , Poliendocrinopatias Autoimunes/tratamento farmacológico , Poliendocrinopatias Autoimunes/mortalidade , Poliendocrinopatias Autoimunes/patologia , Valor Preditivo dos Testes , Sepse/imunologia , Resultado do TratamentoRESUMO
The treatment approach for superficial (stage T1) esophageal adenocarcinoma critically depends on the pre-operative assessment of metastatic risk. Part of that assessment involves evaluation of the primary tumor for pathologic characteristics known to predict nodal metastasis: depth of invasion (intramucosal vs submucosal), angiolymphatic invasion, tumor grade, and tumor size. Tumor budding is a histologic pattern that is associated with poor prognosis in early-stage colorectal adenocarcinoma and a predictor of nodal metastasis in T1 colorectal adenocarcinoma. In a retrospective study, we used a semi-quantitative histologic scoring system to categorize 210 surgically resected, superficial (stage T1) esophageal adenocarcinomas according to the extent of tumor budding (none, focal, and extensive) and also evaluated other known risk factors for nodal metastasis, including depth of invasion, angiolymphatic invasion, tumor grade, and tumor size. We assessed the risk of nodal metastasis associated with tumor budding in univariate analyses and controlled for other risk factors in a multivariate logistic regression model. In all, 41% (24 out of 59) of tumors with extensive tumor budding (tumor budding in ≥3 20X microscopic fields) were metastatic to regional lymph nodes, compared with 10% (12 out of 117) of tumors with no tumor budding, and 15% (5 out of 34) of tumors with focal tumor budding (P<0.001). When controlling for all pathologic risk factors in a multivariate analysis, extensive tumor budding remains an independent risk factor for lymph node metastasis in superficial esophageal adenocarcinoma associated with a 2.5-fold increase (95% CI=1.1-6.3, P=0.039) in the risk of nodal metastasis. Extensive tumor budding is also a poor prognostic factor with respect to overall survival and time to recurrence in univariate and multivariate analyses. As an independent risk factor for nodal metastasis and poor prognosis after esophagectomy, tumor budding should be evaluated in superficial (T1) esophageal adenocarcinoma as a part of a comprehensive pathologic risk assessment.
Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Metástase Linfática/patologia , Adenocarcinoma/mortalidade , Idoso , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de RiscoRESUMO
Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Neoplasias do Apêndice/diagnóstico , Biomarcadores Tumorais/genética , Carcinoma de Células em Anel de Sinete/diagnóstico , Técnicas de Diagnóstico Molecular , Gradação de Tumores/métodos , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/secundário , Neoplasias do Apêndice/classificação , Neoplasias do Apêndice/genética , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/patologia , Biópsia , Carcinoma de Células em Anel de Sinete/classificação , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/mortalidade , Carcinoma de Células em Anel de Sinete/secundário , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Análise Multivariada , Mutação , Invasividade Neoplásica , Pennsylvania , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Medição de Risco , Fatores de Risco , Proteínas ras/genéticaRESUMO
BACKGROUND: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.
Assuntos
Adenocarcinoma/etiologia , Adenocarcinoma/prevenção & controle , Esôfago de Barrett/etiologia , Esôfago de Barrett/prevenção & controle , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/prevenção & controle , Refluxo Gastroesofágico/complicações , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzamidas/farmacologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Proteínas Hedgehog/metabolismo , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Masculino , Quinazolinas/farmacologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptor SmoothenedRESUMO
BACKGROUND: EMR and ablation are increasingly being used alone or in combination for treatment of Barrett's neoplasia. Given a very low rate of lymph node metastasis, endotherapy has become an accepted treatment option for T1a esophageal adenocarcinoma (EAC) with low-risk features. OBJECTIVE: To report our experience of endoscopic management of T1a EAC in a large, tertiary-care center. DESIGN: Retrospective review. SETTING: Tertiary-care referral center. PATIENTS: Patients treated endoscopically for low-risk T1a EAC at our center. INTERVENTION: EMR and endoscopic ablation. MAIN OUTCOME MEASUREMENTS: Death related to esophageal cancer, remission of adenocarcinoma, dysplasia, and intestinal metaplasia. RESULTS: A total of 54 patients underwent endotherapy for low-risk T1a EAC from 2006 to 2012. Mean (± SD) follow-up was 23 (± 16) months, mean (± SD) size of resected adenocarcinoma was 7.1 (± 4.3) mm, and mean (± SD) Barrett's esophagus length was 4.5 (± 3.9) cm. Band-assisted, cap-assisted, and lift and cut EMR were performed in 85%, 11%, and 4% of patients, respectively; 81% underwent additional ablative therapy (radiofrequency ablation 95%, cryotherapy 9%, photodynamic therapy 2%). Complete remission from cancer was achieved in 96%, complete remission from dysplasia in 87%, and complete remission from intestinal metaplasia in 59%. The overall survival was 89%; there were no deaths related to esophageal cancer. LIMITATIONS: Retrospective study. CONCLUSION: Endotherapy for T1a EAC was safe and effective in our American cohort. Endotherapy should be considered primary therapy for appropriate patients with low-risk lesions. Complete Barrett's esophagus eradication after EMR is important to reduce the development of metachronous lesions.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias Esofágicas/cirurgia , Mucosa/cirurgia , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Esofágicas/patologia , Esofagoscopia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.
Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Lesões Pré-Cancerosas , Humanos , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Instabilidade Cromossômica/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Genômica , Progressão da DoençaRESUMO
INTRODUCTION: Objective risk stratification is needed for patients with Barrett's esophagus (BE) to enable risk-aligned management to improve health outcomes. This study evaluated the predictive performance of a tissue systems pathology [TSP-9] test (TissueCypher) vs current clinicopathologic variables in a multicenter cohort of patients with BE. METHODS: Data from 699 patients with BE from 5 published studies on the TSP-9 test were evaluated. Five hundred nine patients did not progress during surveillance, 40 were diagnosed with high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) within 12 months, and 150 progressed to HGD/EAC after 12 months. Age, sex, segment length, hiatal hernia, original and expert pathology review diagnoses, and TSP-9 risk classes were collected. The predictive performance of clinicopathologic variables and the TSP-9 test was compared, and the TSP-9 test was evaluated in clinically relevant patient subsets. RESULTS: The sensitivity of the TSP-9 test in detecting progressors was 62.3% compared with 28.3% for expert-confirmed low-grade dysplasia (LGD), while the original diagnosis abstracted from medical records did not provide any significant risk stratification. The TSP-9 test identified 57% of progressors with nondysplastic Barrett's esophagus (NDBE) ( P < 0.0001). Patients with NDBE who scored TSP-9 high risk progressed at a similar rate (3.2%/yr) to patients with expert-confirmed LGD (3.7%/yr). The TSP-9 test provided significant risk stratification in clinically low-risk patients (NDBE, female, short-segment BE) and clinically high-risk patients (IND/LGD, male, long-segment BE) ( P < 0.0001 for comparison of high-risk classes vs low-risk classes). DISCUSSION: The TSP-9 test predicts risk of progression to HGD/EAC independently of current clinicopathologic variables in patients with BE. The test provides objective risk stratification results that may guide management decisions to improve health outcomes for patients with BE.
Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Humanos , Masculino , Feminino , Esôfago de Barrett/patologia , Progressão da Doença , Neoplasias Esofágicas/patologia , Adenocarcinoma/patologia , HiperplasiaRESUMO
UNLABELLED: Hepatic steatosis is the initial stage of nonalcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant cdipthi559Tg/+ (hi559). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that cdipt is expressed in the developing liver, and its disruption in hi559 mutants abrogates de novo PtdIns synthesis, resulting in hepatomegaly at 5 days postfertilization. The hi559 hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of endoplasmic reticulum stress response (ERSR) genes in hi559 mutants. ER stress markers, including atf6, hspa5, calr, and xbp1, are selectively up-regulated in the mutant liver. The hi559 expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the hi559 hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to hi559, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis. CONCLUSION: cdipt-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of hi559 mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis, and evaluation of novel therapeutics of NAFLD.
Assuntos
CDP-Diacilglicerol-Inositol 3-Fosfatidiltransferase/genética , Retículo Endoplasmático/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Proteínas de Membrana/genética , Fosfatidilinositóis/biossíntese , Estresse Fisiológico , Proteínas de Peixe-Zebra/genética , Animais , Fígado Gorduroso/genética , Hepatócitos/metabolismo , Mutação , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
INTRODUCTION: Intraprocedural rapid onsite evaluation (ROSE) of cytology specimens enhances cytopathology practice. More recently, ROSE diagnoses, like frozen section (FS) diagnoses, have guided immediate clinical decisions. In this study, we evaluated the diagnostic accuracy of definitive ROSE diagnoses in our quality assurance system over a 52-month period. MATERIALS AND METHODS: Cytopathology cases with ROSE from January 2017 to April 2021were retrieved from our laboratory information system. After excluding cases that were deferred or nondiagnostic/unsatisfactory, each definitive ROSE diagnosis (ie, negative for malignant cells or positive for malignant cells) was categorized as having agreement or disagreement with the final diagnosis. For comparison, concordance of FS diagnoses from the same time period were tabulated and compared to those of ROSE diagnoses by using χ2 testing with P < 0.05 considered statistically significant. RESULTS: Of the 1649 ROSE diagnoses, there were 15 disagreements (0.9%) with 1 final moderate interpretive disagreement (0.06%). By comparison, of the 17,469 FS diagnoses, there were 141 disagreements (0.8%) with 49 final moderate or major interpretive disagreements (0.3%). The remaining disagreements were minor. There were no statistically significant differences in the rates of final moderate and major interpretive disagreements. CONCLUSIONS: The final interpretive disagreement rates for definitive ROSE and FS diagnoses were similar in this study. Given the expanding role of ROSE and its use for immediate clinical decisions in some cases, monitoring the accuracy of definitive diagnoses may serve as an initial quality assurance measure.
Assuntos
Biologia Celular , Técnicas Citológicas , Biópsia por Agulha Fina , HumanosRESUMO
We describe the clinical, pathologic and molecular characteristics of a xenograft model of metastatic mucinous appendiceal adenocarcinoma. Tumours from patients with mucinous appendiceal neoplasms were implanted in nude mice and observed for evidence of intraperitoneal tumour growth. Morphologic and immunohistochemical features, temporal growth characteristics relative to controls, and loss of heterozygosity (LOH) at multiple chromosomal alleles were assessed in a successfully engrafted tumour. Two of seventeen implanted tumours successfully engrafted and only one mucinous adenocarcinoma propagated throughout the course of the study. The successful xenograft is morphologically similar to the original tumour, produces abundant extracellular mucin and exhibits non-invasive growth on peritoneal surfaces. The temporal growth characteristics of the xenograft tumour relative to controls reveal that tumour burden can be followed indirectly by measuring the weight or abdominal girth of engrafted animals. The cytokeratin, mucin core protein, CDX2, Ki-67 and p53 expression patterns are identical in the xenograft and resected tumour and are consistent with the expected pattern of protein expression for mucinous adenocarcinoma of the appendix. LOH was found in 1 of 10 informative chromosomal loci (chromosome 10p23) in xenograft tumour cells. Although we were unable to engraft a low-grade appendiceal mucinous neoplasm, the engrafted adenocarcinoma will be useful for future evaluation of novel therapeutic strategies directed at mucinous appendiceal adenocarcinoma and evaluation of strategies for treating widespread, bulky, mucinous peritoneal surface neoplasms. Xenograft tumour enrichment can facilitate molecular studies of appendiceal epithelial neoplasia.
Assuntos
Adenocarcinoma Mucinoso/secundário , Neoplasias do Apêndice/patologia , Neoplasias Peritoneais/secundário , Ensaios Antitumorais Modelo de Xenoenxerto , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/metabolismo , Animais , Neoplasias do Apêndice/genética , Neoplasias do Apêndice/metabolismo , Fator de Transcrição CDX2 , Proliferação de Células , Cromossomos Humanos Par 10 , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Queratinas/metabolismo , Antígeno Ki-67/metabolismo , Perda de Heterozigosidade , Camundongos , Camundongos Nus , Mucinas/metabolismo , Mutação , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Tempo , Carga Tumoral , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/genéticaRESUMO
BACKGROUND & AIMS: Although the cell of origin for pancreatic cancer remains unknown, prior studies have suggested that pancreatic neoplasia may be initiated in progenitor-like cells. To examine the effects of oncogene activation within the pancreatic progenitor pool, we devised a system for real-time visualization of both normal and oncogenic KRAS-expressing pancreatic progenitor cells in living zebrafish embryos. METHODS: By using BAC transgenes under the regulation of ptf1a regulatory elements, we expressed either extended green fluorescent protein (eGFP) alone or eGFP fused to oncogenic KRAS in developing zebrafish pancreas. RESULTS: After their initial specification, normal eGFP-labeled pancreatic progenitor cells were observed to actively migrate away from the forming endodermal gut tube, and subsequently underwent characteristic exocrine differentiation. In contrast, pancreatic progenitor cells expressing oncogenic KRAS underwent normal specification and migration, but failed to differentiate. This block in differentiation resulted in the abnormal persistence of an undifferentiated progenitor pool, and was associated with the subsequent formation of invasive pancreatic cancer. These tumors showed several features in common with the human disease, including evidence of abnormal Hedgehog pathway activation. CONCLUSIONS: These results provide a unique view of the tumor-initiating effects of oncogenic KRAS in a living vertebrate organism, and suggest that zebrafish models of pancreatic cancer may prove useful in advancing our understanding of the human disease.