RESUMEN
This review focuses on the histopathological evaluation of endoscopic mucosal resection (EMR) specimens in Barrett's esophagus, and on the histopathological, biological, and molecular properties of postablation Barrett's esophagus. EMR may be used for both diagnostic and therapeutic purposes. Diagnostic accuracy regarding the grade and stage of neoplasms is improved with the use of EMR, but the value of this technique for treatment is more controversial because of the high prevalence rate of positive margins and the rate of metachronous lesions found elsewhere in the esophagus during follow-up. Ablation techniques, such as argon plasma coagulation, photodynamic therapy, and radiofrequency ablation, are used increasingly for the treatment of Barrett's esophagus and related neoplasms, often in combination with EMR. A common problem after use of these techniques is the development of islands of neosquamous epithelium (NSE) which can overlie buried Barrett's (and/or dysplasia) epithelium. This is, therefore, concealed to the endoscopist's view and may be allowed to progress to cancer without detection. NSE is histologically similar to normal esophageal squamous epithelium and does not possess the molecular aberrations characteristic of Barrett's esophagus. In contrast, residual nonburied Barrett's esophagus shows persistent pathologic and molecular abnormalities and may progress to cancer upon long term follow-up. The biological potential and rate of progression of nonburied residual Barrett's esophagus following ablation is unclear, but some preliminary studies suggest that the risk may decrease. Buried nondysplastic Barrett's esophagus appears to show decreased biological potential and this may be related to protection from the contents of the lumen by the barrier function of the overlying NSE. On the other hand, anecdotal reports have suggested that buried dysplasia may progress to cancer in some instances.
Asunto(s)
Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Esofagoscopía , Esófago/patología , Esófago/cirugía , Lesiones Precancerosas/patología , Displasia del Cuello del Útero/patología , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Esófago de Barrett/genética , Esófago de Barrett/cirugía , Biopsia , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Análisis Mutacional de ADN , Epitelio/patología , Epitelio/cirugía , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirugía , Humanos , Membrana Mucosa/patología , Membrana Mucosa/cirugía , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Lesiones Precancerosas/genética , Lesiones Precancerosas/cirugía , Proteína p53 Supresora de Tumor/genética , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/cirugíaRESUMEN
This review focuses on the pathological features of dysplasia in Barrett's oesophagus. Two categorisation schemes are used for grading dysplasia in the gastrointestinal tract, including Barrett's oesophagus. The inflammatory bowel disease dysplasia morphology study group system is the one most commonly used in the USA. However, some European and most far Eastern countries use the Vienna classification system, which uses the term "non-invasive neoplasia" instead of low-grade dysplasia (LGD) or high-grade dysplasia (HGD) and also uses the term "suspicious for invasive carcinoma" for lesions that show equivocal cytological or architectural features of tissue invasion. The degree of dysplasia is based on a combination of cytological and architectural atypia. However, the precise number of HGD crypts that is necessary to upgrade a biopsy from LGD to HGD has never been investigated and varies widely among expert gastrointestinal pathologists. The extent of dysplasia, particularly LGD, has also been recognised recently as an important prognostic parameter in Barrett's oesophagus. Other problematic areas of dysplasia interpretation include differentiation of regenerating epithelium versus LGD and separating HGD from carcinoma. Dysplasia associated with macroscopically visible lesions, such as ulcers, nodules or polyps, carry a high risk of synchronous or metachronous adenocarcinoma. Recently, immunostaining for alpha-methylacyl-CoA-racemase has been shown to have a high degree of specificity for detection of dysplasia in Barrett's oesophagus and may be used to help distinguish negative from positive biopsies in this condition. In this review, the problematic areas in dysplasia interpretation are outlined and a specific approach to these issues is discussed.
Asunto(s)
Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Lesiones Precancerosas/patología , Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Invasividad NeoplásicaRESUMEN
This review summarizes some of the common diagnostic problems encountered by pathologists when evaluating patients with chronic colitis and in whom inflammatory bowel disease (IBD) is either suspected or within the differential diagnosis. Both ulcerative colitis (UC) and Crohn's disease (CD) show characteristic, but non-specific, pathological features that may overlap and result in a diagnosis of 'indeterminate colitis' (IC). However, other reasons why pathologists may entertain a diagnosis of IC include failure to recognize or accept certain 'hardcore' histological features as indicative of CD, an attempt to classify cases of chronic colitis based on mucosal biopsy material or in the absence of adequate clinical and radiographic information, and the presence of other disease processes that mask, or mimic, IBD. In addition, some cases of UC may show unusual CD-like features, such as discontinuous or patchy disease, ileal inflammation, extracolonic inflammation, granulomatous inflammation in response to ruptured crypts, aphthous ulcers, or transmural inflammation. Furthermore, other forms of colitis, such as microscopic colitis, diverticulitis and diversion colitis may, on occasion, also show IBD-like changes. The clinical and pathological features that aid in the distinction between these entities, and others, are covered in detail in this review.
Asunto(s)
Colon/patología , Enfermedades Inflamatorias del Intestino/diagnóstico , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/diagnóstico , Diagnóstico Diferencial , HumanosRESUMEN
p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract. The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues. In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18. In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The DeltaN isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis. These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium.
Asunto(s)
Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Carcinoma de Células Escamosas/metabolismo , Sistema Digestivo/metabolismo , Neoplasias Esofágicas/metabolismo , Esófago/metabolismo , Proteínas de la Membrana , Fosfoproteínas/metabolismo , Transactivadores/metabolismo , Adenocarcinoma/genética , Esófago de Barrett/genética , Carcinoma de Células Escamosas/genética , Proteínas de Unión al ADN , Epitelio/metabolismo , Enfermedades del Esófago/genética , Enfermedades del Esófago/metabolismo , Enfermedades del Esófago/patología , Neoplasias Esofágicas/genética , Esófago/patología , Genes Supresores de Tumor , Humanos , Inmunohistoquímica , Queratinas/inmunología , Queratinas/metabolismo , Antígeno Ki-67/inmunología , Antígeno Ki-67/metabolismo , Metaplasia/genética , Metaplasia/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , ARN Mensajero/biosíntesis , Estudios Retrospectivos , Transactivadores/genética , Transactivadores/inmunología , Factores de Transcripción , Transcripción Genética , Proteína p53 Supresora de Tumor/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de TumorRESUMEN
Expression of cytokeratin (CK) 7 and 20 is commonly used to help distinguish adenocarcinomas from different sites. Thyroid transcription factor 1 (TTF-1) is a 38-kd protein, located primarily in the nucleus of type 2 pneumocytes and clara cells. TTF-1 has been shown to be present in a variety of lung and thyroid tumors and in pulmonary small-cell carcinomas. Carcinoid tumors from the lung and the gastrointestinal (GI) tract are histologically similar and thus are difficult to differentiate from each other based on histologic criteria. Pancreatic endocrine tumors (PET) have a similar histologic appearance to these other tumors. The purpose of this study was to determine the efficacy of differentiating these 3 groups of tumors by their expression of CK7, CK20, and TTF-1. Routinely processed paraffin-embedded tissue sections from 62 carcinoid tumors (lung, 16; gastrointestinal [GI] tract, 46) and 12 PETs were immunohistochemically stained for CK7, CK20, and TTF-1. The degree of expression in each tumor was graded as 1+ (1% to 10% of cells positive), 2+ (11% to 25%), 3+ (26% to 50%), and 4+ (>50%). The data were compared between tumor types and between carcinoid tumors from the various locations in the GI tract (stomach, 8; small intestine, 19; large intestine, 17; appendix, 2). CK7 was expressed in 10 (63%) of 16 pulmonary carcinoid tumors and only 5 (11%) of 46 GI carcinoid tumors (P <.001). Pancreatic endocrine tumors showed CK7 positivity in 6 (50%) of 12 cases, which was similar to the findings in lung carcinoids and significantly higher than in GI carcinoids (P <.01). CK20 was expressed in 0 (0%) of 16 pulmonary carcinoid tumors, in contrast to 24% and 33% of GI carcinoid tumors (P <.05) and PETs (P <.05), respectively. TTF-1 expression was highly specific for pulmonary carcinoid tumors. This peptide was present in 11 (69%) of 16 pulmonary carcinoid tumors and in only 1 (2%) of 46 and 0 (0%) of 12 GI carcinoid tumors (P <.001) and PETs (P <.001), respectively. A CK7(+)/CK20(-)/TTF-1(+) immunopanel result was moderately sensitive (sensitivity, 50%), and highly specific (specificity, 100%), for a diagnosis of pulmonary carcinoid tumor. CK7, CK20, and TTF-1 did not differ significantly between carcinoid tumors located in different sites of the GI tract. However, a trend was observed toward a lower prevalence of CK20 positivity in gastric tumors (P =.06) than in GI carcinoid tumors from the small intestine, colon, or appendix. Expression of CK7 and CK20, and particularly TTF-1, may be useful in distinguishing pulmonary from GI carcinoid tumors and PETs, especially when evaluated as a panel of markers. TTF-1 is highly specific for pulmonary carcinoid tumors.
Asunto(s)
Tumor Carcinoide/metabolismo , Neoplasias Gastrointestinales/metabolismo , Insulinoma/metabolismo , Proteínas de Filamentos Intermediarios/biosíntesis , Queratinas/biosíntesis , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/biosíntesis , Factores de Transcripción/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Tumor Carcinoide/química , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/secundario , Diagnóstico Diferencial , Femenino , Neoplasias Gastrointestinales/química , Neoplasias Gastrointestinales/diagnóstico , Humanos , Técnicas para Inmunoenzimas , Insulinoma/química , Insulinoma/secundario , Proteínas de Filamentos Intermediarios/análisis , Queratina-20 , Queratina-7 , Queratinas/análisis , Neoplasias Pulmonares/química , Neoplasias Pulmonares/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Nucleares/análisis , Factor Nuclear Tiroideo 1 , Factores de Transcripción/análisisRESUMEN
Hyperplastic polyps of the colon are the most common type of benign colonic polyp. Rarely, these polyps may show misplaced epithelium within the submucosa, thereby simulating an adenoma with pseudoinvasion or even an adenocarcinoma. In this study, we describe the clinical, pathologic, and immunophenotypic features of 19 hyperplastic polyps with misplaced epithelium to identify potential diagnostic pitfalls and gain insight into their pathogenesis. Routinely processed polypectomy specimens from 12 patients with 19 hyperplastic polyps containing foci of misplaced epithelium were evaluated for a variety of morphologic features including pattern and extent of submucosal involvement, continuity of the submucosal epithelium with the mucosa, presence of recent or remote hemorrhage, inflammation, association of misplaced epithelium with lymphoid aggregates, inflammation, and defects in the muscularis mucosae. Clinical and endoscopic data were obtained and correlated with the histologic findings. Immunoperoxidase stains (ABC method) for collagen IV (basement membrane marker), MIB-1 (proliferation marker), and E-cadherin (intercellular adhesion protein) were performed in all cases. The study group consisted of five males and seven females ranging in age from to 52 to 73 years (mean: 63 y). All of the polyps were located in the rectum or sigmoid colon, and their mean size was 0.5 cm (range: 0.2 to 1.0 cm). Most showed misplaced epithelium in a lobular (26%) or a mixed pattern consisting of lobules and irregularly distributed crypts (63%) that, upon deeper levels, was almost always continuous with the mucosal portion of the polyps (95%). Defects in the muscularis mucosae and splaying of the muscle fibers around misplaced epithelium were seen in all cases. Lymphoid aggregates were present adjacent to foci of misplaced epithelium in 37% of cases. Fresh hemorrhage, vascular congestion, and hemosiderin deposits were present in 79, 53, and 42% of cases, respectively. Strong and uniform staining of the misplaced epithelium for MIB-1 and E-cadherin was demonstrated in all cases, similar to that seen in the lower third of the mucosal portion of the polyps. A continuous collagen IV basement membrane pattern of staining was noted around all foci of misplaced epithelium. Hyperplastic polyps with misplaced epithelium probably occur secondary to trauma-induced protrusion of glands through breaks in the muscularis mucosae. Pathologists should be aware of this entity to avoid diagnostic confusion with other, more serious lesions, such as adenomas with pseudoinvasion or well-differentiated adenocarcinoma.
Asunto(s)
Colon/patología , Pólipos del Colon/patología , Anciano , Colon/química , Pólipos del Colon/metabolismo , Colonoscopía , Epitelio/patología , Femenino , Humanos , Hiperplasia , Inmunohistoquímica , Mucosa Intestinal/patología , Masculino , Persona de Mediana EdadRESUMEN
Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.
Asunto(s)
Apoptosis/fisiología , Síndrome de Peutz-Jeghers/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Células Cultivadas , Expresión Génica , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Intestino Delgado/metabolismo , Intestino Delgado/patología , Mitocondrias/metabolismo , Mutación/fisiología , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/patología , FosforilaciónRESUMEN
Preoperative chemotherapy combined with radiotherapy (chemrad) is a common type of neoadjuvant treatment for esophageal adenocarcinoma or squamous cell carcinoma. The purpose of this study was to describe the clinical, histologic, proliferative (MIB-1), and oncogenetic (p53) features of 15 patients with gastric dysplasia-like epithelial atypical changes associated with preoperative chemrad for esophageal cancer. Two of these cases were initially misinterpreted as dysplasia, which led to partial gastrectomy. The findings were compared with 12 age- and sex-matched patients with known gastric dysplasia. Cases with gastric dysplasia-like epithelial atypia were significantly associated with a flat gross appearance, a patchy distribution, foveolar and gland involvement, surface maturation, an open nuclear chromatin pattern with prominent nucleoli, retention of nuclear polarity, mitoses confined to the pits, lack of atypical mitoses, cytoplasmic hypereosinophila and/or vacuolization, a lack of association with intestinal metaplasia, and finally, irregular glandular microcystic change, in comparison to the dysplasia controls. Furthermore, the study cases showed MIB-1 positivity restricted to the deep foveolar epithelium and an absence of p53 staining in 14 of 15 cases, in contrast to the dysplasia controls, in which MIB-1 stained both the deep and superficial foveolar epithelium and surface epithelium, and p53 was positive in all cases (100%). In summary, a number of histologic and immunohistochemical features may distinguish gastric dysplasia-like epithelial atypia associated with chemrad for esophageal cancer from true dysplasia. Pathologists should be aware of this entity and its histologic and immunohistochemical features to avoid misinterpretation and prevent unnecessary treatment.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Terapia Neoadyuvante/efectos adversos , Traumatismos por Radiación , Adenocarcinoma/química , Adenocarcinoma/patología , Adulto , Anciano , Antígenos Nucleares , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patología , Epitelio/química , Epitelio/efectos de los fármacos , Epitelio/patología , Epitelio/efectos de la radiación , Neoplasias Esofágicas/química , Neoplasias Esofágicas/patología , Femenino , Mucosa Gástrica/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/efectos de la radiación , Humanos , Inmunohistoquímica , Antígeno Ki-67 , Masculino , Persona de Mediana Edad , Proteínas Nucleares/análisis , Proteína p53 Supresora de Tumor/análisisRESUMEN
A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barrett's esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium. Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation. Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGFalpha, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium. Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal "squamoid" cells, CK 7, 8/18, 19, and 20 in the superficial "columnar" cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGFalpha, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa. These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.
Asunto(s)
Esófago de Barrett/patología , Unión Esofagogástrica/patología , Mucosa Gástrica/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/etiología , Esófago de Barrett/metabolismo , Biomarcadores/análisis , Biopsia , Epitelio/anatomía & histología , Epitelio/metabolismo , Epitelio/patología , Unión Esofagogástrica/anatomía & histología , Unión Esofagogástrica/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Mucosa Gástrica/anatomía & histología , Mucosa Gástrica/metabolismo , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/patología , Humanos , Queratinas/metabolismo , Masculino , Metaplasia/etiología , Metaplasia/metabolismo , Metaplasia/patología , Persona de Mediana Edad , Mucinas/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Microsatellite instability (MSI) has been documented in malignancies associated with hereditary nonpolyposis colon carcinoma and in sporadic malignancies of the colon, stomach, and endometrium. In these malignancies, MSI is associated with defects in the DNA mismatch repair enzymes hMSH2 and hMLH1. Defects in these enzymes result in a phenotype characterized by instability of multiple microsatellite repeat sequences throughout the genome. This study sought to determine the prevalence of MSI in 80 primary Barrett esophagus-associated adenocarcinomas (BEAd) and to examine the relation of MSI with the clinical and pathologic features of the tumors. METHODS: Eighty BEAd were evaluated for the presence of MSI by using the microsatellite markers BAT25, BAT26, D10S219, D10S541, and D10S551. These tumors also were evaluated for immunohistochemical expression of hMSH2 and hMLH1. RESULTS: High levels of MSI were not found in any of the tumors examined. Furthermore, immunohistochemical expression of hMSH2 and hMLH1 was retained in all cases evaluated. Evidence of low level MSI was found in 16% of tumors. In none of these tumors, however, was MSI present in more than two of five loci. The presence of MSI did not correlate with patient age, tumor stage, degree of differentiation, or with patient survival. CONCLUSIONS: High level MSI and loss of hMLH1/hMSH2 expression is uncommon in BEAd. A subset of BEAd demonstrate low level MSI. The presence of low level MSI was not associated with the clinicopathologic features of the tumors examined.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Neoplasias Esofágicas/genética , Repeticiones de Microsatélite/genética , Proteínas de Neoplasias/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Adenocarcinoma/patología , Adulto , Anciano , Esófago de Barrett/complicaciones , Proteínas Portadoras , Estudios de Cohortes , Neoplasias Esofágicas/patología , Femenino , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Prevalencia , Pronóstico , Análisis de SupervivenciaRESUMEN
PTEN is a putative tumour suppressor gene located on chromosome band 10q23. Mutations in PTEN have been identified in numerous human malignancies, including cancers of the brain, endometrium, ovary, and prostate. In this study, we screened 80 Barrett's oesophagus-associated adenocarcinomas (BOAd) for loss of heterozygosity (LOH) at 10q23, using the microsatellite markers D10S541, D10S219, and D10S551. Tumours demonstrating LOH were then screened for the presence or absence of PTEN mutations. LOH at one or more loci was identified in 17/80 (21%) cases. In none of these cases did we detect mutations in PTEN. The presence of LOH did not correlate with patient age, tumour stage, degree of differentiation, presence of perineural or vascular invasion, or overall survival. We conclude that LOH at chromosome 10q23 is uncommon in BOAd, is not associated with mutations in the PTEN tumour suppressor gene, and does not correlate with the clinical or pathologic features of these tumours. It is possible that PTEN is inactivated through other mechanisms in BOAd.
Asunto(s)
Adenocarcinoma/genética , Alelos , Esófago de Barrett/genética , Cromosomas Humanos Par 10 , Genes Supresores de Tumor , Monoéster Fosfórico Hidrolasas/genética , Proteínas Supresoras de Tumor , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTENRESUMEN
The pathogenesis of short segment Barrett's esophagus (SSBE) and intestinal metaplasia (IM) of the gastroesophageal junction (IMGEJ) are poorly understood. Also, these conditions are difficult to distinguish from one another based solely on endoscopic and pathologic criteria. Therefore, the aim of this study was to evaluate the immunophenotypic features of SSBE and IMGEJ and to compare the results with lesions of known etiologies: long segment BE (LSBE) caused by reflux disease and Helicobacter pylori-induced IM of the gastric antrum (IMGA). Routinely processed mucosal biopsy specimens from 11 patients with LSBE, 17 with SSBE, 10 with IMGEJ, 16 with IMGA, 17 with a normal nonmetaplastic GEJ, and 7 patients with a normal gastric antrum were immunohistochemically stained with monoclonal antibodies to: Das1, an antibody shown to react specifically with colonic goblet cells; 45M1, an antibody that recognizes the M1 gastric mucin antigen; and cytokeratin (CK) 7 and 20, antibodies that have previously been reported to show specific staining patterns in BE versus IMGA. Also evaluated was nonintestinalized mucinous epithelium from LSBE, SSBE, and also the normal GEJ and gastric antrum. LSBE, SSBE, and IMGEJ showed similar prevalences of Das1 (91% versus 88% versus 100%) and 45M1 reactivity (100% versus 100% versus 100%), and a similar pattern of CK7/20 reactivity (diffuse strong CK7 staining of the surface and crypt epithelium, and strong surface and superficial crypt CK20 staining) (91% versus 94% versus 90%). In contrast, although 45M1 reactivity in IMGA (93%) was similar to that of the other three groups, IMGA showed a significantly lower prevalence of Das positivity (13%, p < 0.001), and only a 14% prevalence of the CK7/20 staining pattern that was predominant in the other three groups (p < 0.001). Das1, 45M1, and CK7/20 staining were similar in nonintestinalized "cardia-type" mucinous epithelium from LSBE, SSBE, and the GEJ, but all were distinct from the normal gastric antrum. In summary, the immunophenotypic features of SSBE and IMGEJ are similar and closely resemble those seen in classic LSBE, but are distinct from IMGA. This may indicate that IM in LSBE, SSBE and at the GEJ have similar biologic properties. Based on our data, SSBE and IMGEJ cannot be distinguished on the basis of their immunophenotype.
Asunto(s)
Esófago de Barrett/patología , Unión Esofagogástrica/patología , Anticuerpos , Esófago de Barrett/inmunología , Biomarcadores/análisis , Unión Esofagogástrica/inmunología , Unión Esofagogástrica/virología , Reflujo Gastroesofágico/inmunología , Reflujo Gastroesofágico/patología , Humanos , Inmunofenotipificación/métodos , Proteínas de Filamentos Intermediarios/análisis , Queratina-20 , Queratina-7 , Queratinas/análisis , Metaplasia/inmunología , Metaplasia/patología , Estudios RetrospectivosRESUMEN
OBJECTIVE: We recently identified a distinctive type of multilayered epithelium in two patients with Barrett's esophagus, which shows morphological characteristics of both squamous and columnar epithelium. This study was performed to prospectively evaluate the prevalence of multilayered epithelium in patients with Barrett's esophagus. METHODS: Mucosal biopsies were obtained from the squamocolumnar junction (Z-line) of 58 patients with endoscopic evidence of esophageal columnar epithelium and from the gastroesophageal junction in 21 patients without endoscopic evidence of esophageal columnar epithelium. Specimens were evaluated for the presence of multilayered epithelium and goblet cells. RESULTS: Twenty-four of 58 (41%) of the patients with endoscopic evidence of esophageal columnar epithelium had multilayered epithelium compared with only one of 21 patients (5%) in the control group (p = 0.005). Of the 58 patients in the study group, 43 had goblet cell metaplasia and 15 did not (p < 0.001). Only patients with goblet cell metaplasia had multilayered epithelium. Shorter lengths of columnar epithelium were noted in the 24 patients with goblet cells and multilayered epithelium compared with the 19 patients with goblet cells and no multilayered epithelium (p < 0.05). CONCLUSIONS: Multilayered epithelium is strongly associated with goblet cell metaplasia in patients with endoscopic evidence of esophageal columnar epithelium. These data support the hypothesis that multilayered epithelium may represent a transitional stage in the development of Barrett's esophagus.
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Esófago de Barrett/fisiopatología , Esófago/patología , Anciano , Biopsia , Epitelio/patología , Femenino , Células Caliciformes/patología , Humanos , Masculino , Metaplasia , Persona de Mediana Edad , Estudios Prospectivos , Valores de ReferenciaRESUMEN
UNLABELLED: Several prior studies have suggested that 80% of deaths in acute pancreatitis occur late as a result of pan-creatic infection. Others have suggested that approx half of deaths occur early as a result of multisystem organ failure. The aim of the present study was to determine the timing of mortality of acute pancreatitis at a large tertiary-care hospital in the United States. METHODS: Patients with a diagnosis of acute pancreatitis (ICD-9 code 577.0) admitted to Brigham and Women's Hospital from October 1, 1982 to June 30, 1995 were retrospectively studied to determine total mortality, frequency of early vs late deaths, and clinical features of patients with early (< or = 14 d after admission) or late deaths (> 14 d after admission). RESULTS: The overall mortality of acute pancreatitis was 2.1% (17 deaths among 805 patients). Eight deaths (47%) occurred within the first 14 d of hospitalization (median d 8, range 1-11 d), whereas 9 occurred after 14 d (median d 56, range 19-81). Early deaths resulted primarily from organ failure. Late deaths occurred postoperatively in 8 patients with infected or sterile necrosis and 1 patient with infected necrosis treated medically. CONCLUSION: Approximately half of deaths in acute pancreatitis occur within the first 14 d owing to organ failure and the remainder of deaths occur later because of complications associated with necrotizing pancreatitis. Improvement in mortality in the future will require innovative approaches to counteract early organ failure and late complications of necrotizing pancreatitis.
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Pancreatitis/mortalidad , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hospitalización , Humanos , Infecciones/complicaciones , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/mortalidad , Pancreatitis/complicaciones , Pancreatitis/cirugía , Pancreatitis Aguda Necrotizante/microbiología , Pancreatitis Aguda Necrotizante/mortalidad , Complicaciones Posoperatorias/mortalidad , Estudios Retrospectivos , Análisis de Supervivencia , Factores de TiempoRESUMEN
Recent molecular studies have shown that there are differences in the prevalence and timing of certain molecular events between chronic ulcerative colitis (CUC)-associated dysplastic lesions and non-CUC-related sporadic adenomas. However, little is known regarding the molecular features of a specific subtype of CUC-related dysplasia-associated lesion or mass (DALM) that clinically, endoscopically, and pathologically resemble sporadic adenomas, and whether these lesions can be separated from non-CUC-related sporadic adenomas on the basis of their molecular genotype. Therefore, the purpose of this study was to evaluate loss of heterozygosity (LOH) of 3p, APC, and p16 in a specific group of CUC-associated "adenoma-like" DALMs and to compare the results of this tumor with those in a well-defined group of CUC-associated non-adenoma-like DALMs and non-CUC-associated sporadic adenomas. Polypectomy or resection specimens from 21 CUC patients with an adenoma-like DALM, 8 CUC patients with at least one nonadenoma-like DALM (12 lesions in total), and 23 non-CUC patients with a sporadic adenoma were evaluated for LOH of 3p, APC, and p16 by PCR analysis. The results were compared among the three different study groups and correlated with the clinical features of the patients and the pathology of their tumors. Chronic ulcerative colitis-associated adenoma-like DALMs showed LOH of 3p in five of 18 (28%) cases. This value was not significantly different from the 5% of non-CUC sporadic adenomas (p = 0.14) that were positive. However, 50% of CUC-associated non-adenoma-like DALMs were positive for LOH of 3p, and this value was significantly higher (p = 0.01) than the other groups. The frequency of LOH of APC did not differ significantly between the three patient groups (33%, 33%, and 43% in the three groups, respectively). Similar to the 3p results, CUC-associated adenoma-like DALMs and non-CUC-associated sporadic adenomas showed a similar low frequency of positivity for LOH of p16 (5% and 4%, respectively) in comparison to 56% of CUC-associated non-adenoma-like DALMs (p = 0.003). For all markers, no significant differences were detected in the CUC-associated adenoma-like DALM group between lesions that occurred within colitis compared with those that occurred in areas not involved by colitis. Chronic ulcerative colitis-associated non-adenoma-like DALMs have a different molecular genotype than CUC-related adenoma-like DALMs and non-CUC sporadic adenomas. Our data also suggests that the latter two groups of neoplasms may in fact represent a similar, if not identical, pathogenetic entity.
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Pólipos Adenomatosos/genética , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/genética , Neoplasias del Colon/genética , Pólipos del Colon/genética , Pérdida de Heterocigocidad/genética , Pólipos Adenomatosos/etiología , Pólipos Adenomatosos/patología , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 3/genética , Colitis Ulcerosa/patología , Neoplasias del Colon/etiología , Neoplasias del Colon/patología , Pólipos del Colon/etiología , Pólipos del Colon/patología , Femenino , Genes APC/genética , Genes p16/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Polyps with epithelial dysplasia in ulcerative colitis (UC) represent either dysplasia-associated lesions or masses (DALMs) or sporadic adenomas. DALMs are frequently associated with associated carcinoma and are an indication for colectomy. Removal of the polyp is treatment of choice for sporadic adenomas. Differentiating between these 2 lesions is not always easy. The goal of this study was to distinguish DALMs from adenomas in patients with UC on a genetic basis. We evaluated genetic alterations in DALMs and compared them with a previously published set of dysplastic polyps in patients with UC that were considered adenomas for the following reasons: (1) polyps were located outside of current active disease; (2) polyps had histological features of sporadic adenomas; and (3) patients displayed a uneventful follow-up after polypectomy (UC-adenomas). In addition, adenomas not associated with UC were studied. Genetic alterations on chromosome 3p were assessed for the markers D3S1766, D3S2409, and D3S2387. LOH with or without microsatellite instability was found in 70%, 37%, and 57% of cases of DALM, respectively. In contrast, UC-adenomas lesions exhibited genetic alterations in 8.3%, 11.7%, and 15.3% for the respective markers. Spontaneous adenomas exhibited genetic alterations in 10.5%, 7.1%, and 0% of cases, which were not significantly different from the UC-adenoma results. These results indicate that UC-adenomas are genetically and biologically similar to sporadic adenomas and that UC-adenomas may biologically represent sporadic adenomas, supporting on a genetic basis the criteria chosen to diagnose adenomas in UC. Genetic markers on chromosome 3p may be useful in the differential diagnosis between DALM and UC-adenomas.
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Adenoma/diagnóstico , Colitis Ulcerosa/patología , Colon/patología , Neoplasias del Colon/diagnóstico , Adenoma/genética , Adenoma/cirugía , Adulto , Anciano , Cromosomas Humanos Par 3/genética , Colitis Ulcerosa/genética , Colitis Ulcerosa/cirugía , Colon/cirugía , Neoplasias del Colon/genética , Neoplasias del Colon/cirugía , Cartilla de ADN/química , ADN de Neoplasias/análisis , Diagnóstico Diferencial , Marcadores Genéticos , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
A variety of prognostic markers have been related to decreased patient survival in patients with epithelial malignancies. These include expression of the homotypic adhesion molecule E-cadherin (ECAD) and the hyaluronic acid receptor CD44. Expression of ECAD and CD44 was evaluated in Barrett's-associated adenocarcinoma (BAd) from 67 patients. Expression was determined by immunoperoxidase staining and graded semiquantitatively based on the proportion of positively stained cells. These data were then correlated with clinical and pathological parameters, including the presence or absence of chemoradiotherapy (chemrad) and patient survival. There were 56 men and 11 women (mean age, 62 years). Thirty-nine (58%) patients received preoperative chemrad. ECAD expression was detected in all (100%) tumors. The ECAD staining grade did not correlate with other pathological features of the tumors. However, ECAD staining was significantly increased in BAd of patients who received chemrad (P = .003), in comparison with those who did not, and in individual patients when prechemrad biopsies and postchemrad resection specimens were compared (P = .04). In terms of prognosis, increased ECAD expression was associated with shortened patient survival only in BAd patients who had received chemrad (univariate analysis of chemrad patients with stage I and II BAd, P = .02). ECAD expression was not significantly associated with survival in BAd patients who did not receive chemrad. CD44 expression was detected in 88% of cases. CD44 expression did not correlate with any of the pathological features of the tumors or with chemrad status. Increased expression of CD44 was significantly associated with shortened patient survival in chemrad patients only (univariate analysis P = .03, multivariate analysis P = .04), although a strong trend was observed when all patients were analyzed regardless of chemrad status (P = .07). The results of this study indicate that chemrad alters the expression of ECAD in BAd. Thus, the prognostic utility of ECAD expression must be evaluated in the context of chemrad status. CD44 also may be a valuable prognostic marker in BAd.
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Adenocarcinoma/terapia , Esófago de Barrett/terapia , Biomarcadores de Tumor/biosíntesis , Cadherinas/biosíntesis , Neoplasias Esofágicas/terapia , Receptores de Hialuranos/biosíntesis , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios , Pronóstico , Radioterapia AdyuvanteRESUMEN
The HER-2/neu oncogene is localized to chromosome 17q and shares significant homology with the epidermal growth factor receptor. HER-2/neu protein overexpression has been associated with poor prognosis in a variety of tumors, but its significance in Barrett's esophagus-associated adenocarcinoma (BEAd) is unknown. Therefore, the aim of this study was to evaluate the prevalence and prognostic value of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) in 63 cases of BEAd. Routinely processed tissue sections from resection specimens of 63 patients with BEAd (M/F ratio, 10:1; mean age, 63 years) were assayed for HER-2/neu gene amplification by FISH using the Ventana unique sequence probe (Ventana Medical Systems, Inc, Tuscon, AZ). FISH results were correlated with the pathological features of the tumors and with patient survival. Clinical follow-up data were available for 54 patients (mean follow-up, 31 months [range, 1 to 152 months]). The HER-2/ neu gene was amplified in 12 of 63 (19%) cases. The presence of HER-2/neu gene amplification showed a trend toward a correlation with depth of tumor invasion (P = .07), lymph node metastasis (P = .13), and pathological stage (P = .14), but did not correlate with any of the other pathological features, such as degree of differentiation or tumor size. On both univariate and multivariate analysis, HER-2/neu gene amplification was associated with shortened survival (P = .03). HER-2/neu oncogene amplification, as determined by FISH, correlates with shortened patient survival and independently predicts poor outcome in patients with BEAd.
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Adenocarcinoma/genética , Esófago de Barrett/complicaciones , Neoplasias Esofágicas/genética , Amplificación de Genes , Receptor ErbB-2/genética , Adenocarcinoma/etiología , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/fisiopatología , Femenino , Predicción , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
BACKGROUND & AIMS: Chronic ulcerative colitis (CUC)-associated adenoma-like DALMs (dysplasia-associated lesions or masses) pose a difficult clinical problem to both gastroenterologists and pathologists because they are difficult to distinguish endoscopically and pathologically from sporadic adenomas that develop coincidentally in patients with CUC. The aim of this study was to evaluate the outcome of CUC patients with an adenoma-like DALM treated conservatively and to compare the findings with CUC patients with a coincidental sporadic adenoma. METHODS: Clinical, endoscopic, and pathological features and outcome of 24 CUC patients with an adenoma-like DALM were compared with those of 10 CUC patients with a coincidental sporadic adenoma and 49 non-CUC (control) patients with a sporadic adenoma. Patients were followed up for a mean of 42.4 and 41.2 months for the 2 CUC groups, respectively, and 37.0 months for the non-CUC controls by endoscopic surveillance. RESULTS: Of the 24 CUC patients with adenoma-like DALMs (male/female ratio, 14/10; mean age, 61.5 years; mean duration of colitis, 10.4 years), 14 (58%) developed further adenoma-like DALMs within the follow-up interval. Only 1 patient (4%) developed an isolated focus of low-grade dysplasia, and none developed adenocarcinoma. Five of 10 (50%) CUC patients with sporadic adenomas developed further adenomas, and none of the patients in this group developed either dysplasia or adenocarcinoma. Of the 49 non-CUC control patients, 39% developed further adenomas. CONCLUSIONS: CUC patients who develop an adenoma-like DALM that endoscopically and histologically resembles a sporadic adenoma, regardless of its location (either within or outside areas of documented colitis), may be treated with polypectomy and endoscopic surveillance because of its relatively benign course.
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Adenoma/cirugía , Colitis Ulcerosa/cirugía , Pólipos del Colon/cirugía , Adenoma/diagnóstico , Adenoma/etiología , Adenoma/patología , Enfermedad Crónica , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/patología , Pólipos del Colon/etiología , Pólipos del Colon/patología , Colonoscopía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The cyclin-dependent kinase inhibitor p27 is a negative regulator of the transition from G1 to S phase of the cell cycle, protects against inflammatory injury and promotes epithelial differentiation. Because p27 protein has been shown to be abnormally expressed both in dysplasia associated with Barrett's esophagus and in sporadic colorectal adenomas, we used immunohistochemistry to evaluate p27 expression in inflammatory bowel disease (IBD)-associated dysplasia and carcinomas. Normal, inflamed, and transitional mucosa, sporadic adenomas, and sporadic colonic carcinomas were studied as controls. In normal colonic epithelium p27 expression was restricted to the superficial, terminally differentiated cells. In colitic and inflamed diverticular mucosa p27 was expressed in the base of the crypts in 86 and 70% of cases, respectively. Similarly, in transitional mucosa adjacent to sporadic carcinomas p27 was expressed in the base of the crypts in all cases. Strong p27 expression extended more frequently from the base of the crypts to superficial cells in IBD-associated dysplasia than in sporadic adenomas (P < 0.007). Twenty of 20 (100%) IBD-associated carcinomas showed low p27 expression (<50% nuclei positive) compared to 6 of 20 (30%) stage-matched sporadic colorectal carcinomas (P < 0.001). We conclude (i) aberrant p27 protein expression in inflamed and IBD-associated nondysplastic mucosa is indistinguishable from that found in transitional mucosa adjacent to sporadic carcinomas; (ii) p27 is overexpressed in dysplastic lesions, perhaps as an attempt to counterbalance proliferative stimuli; and (iii) IBD-associated colorectal carcinomas have significantly lower p27 expression, commonly associated with poor prognosis, than stage-matched sporadic colorectal carcinomas. These findings further substantiate the existence of divergent molecular pathogenetic pathways between these types of carcinomas and suggest an intrinsically more aggressive behavior of IBD-associated colon carcinomas compared to sporadic ones.