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McDonald SAC, Lavery D, Wright NA, Jansen M. Barrett oesophagus: lessons on its origins from the lesion itself. Nat Rev Gastroenterol Hepatol 2015; 12:50-60. [PMID: 25365976 DOI: 10.1038/nrgastro.2014.181] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Barrett oesophagus develops when the lower oesophageal squamous epithelium is replaced with columnar epithelium, which shows both intestinal and gastric differentiation. No consensus has been reached on the origin of Barrett oesophagus. Theories include a direct origin from the oesophageal-stratified squamous epithelium, or by proximal migration of the gastric cardiac epithelium with subsequent intestinalization. Variations of this theory suggest the origin is a distinctive cell at the squamocolumnar junction, the oesophageal gland ducts, or circulating bone-marrow-derived cells. Much of the supporting evidence comes from experimental models and not from studies of Barrett mucosa. In this Perspectives article, we look at the Barrett lesion itself: at its phenotype, its complexity, its clonal architecture and its stem cell organization. We conclude that Barrett glands are unique structures, but share many similarities with gastric glands undergoing the process of intestinal metaplasia. We conclude that current evidence most strongly supports an origin from stem cells in the cardia.
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Affiliation(s)
- Stuart A C McDonald
- Centre for Tumour Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1 2AD, UK
| | - Danielle Lavery
- Centre for Tumour Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1 2AD, UK
| | - Nicholas A Wright
- Centre for Tumour Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1 2AD, UK
| | - Marnix Jansen
- Centre for Tumour Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1 2AD, UK
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Wiseman EF, Ang YS. Risk factors for neoplastic progression in Barrett’s esophagus. World J Gastroenterol 2011; 17:3672-83. [PMID: 21990948 PMCID: PMC3181452 DOI: 10.3748/wjg.v17.i32.3672] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 10/11/2010] [Accepted: 10/18/2010] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a “metaplasia-dysplasia-carcinoma” (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available.
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Transthoracic esophagectomy of adenocarcinoma in Barrett’s esophagus in Japanese patients: analysis of localization of lymph node metastases in 19 cases. Esophagus 2010. [DOI: 10.1007/s10388-010-0237-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
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Langer R, Feith M, Siewert JR, Wester HJ, Hoefler H. Expression and clinical significance of glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus. BMC Cancer 2008; 8:70. [PMID: 18331622 PMCID: PMC2270853 DOI: 10.1186/1471-2407-8-70] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 03/10/2008] [Indexed: 01/01/2023] Open
Abstract
Background Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis. Methods Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival. Results GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome. GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031). Conclusion We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.
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Affiliation(s)
- Rupert Langer
- Institute of Pathology, TU München, München, Germany.
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von Rahden BHA, Stein HJ. Barrett's esophagus with high-grade intraepithelial neoplasia: observation, ablation or resection? Eur Surg 2007. [DOI: 10.1007/s10353-007-0337-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
Surgical resection with lymphadenectomy is the mainstay of treatment for all resectable esophagogastric junction tumors, prior to systemic generalization of the disease. This makes accurate pre-treatment staging and classification of the tumors most demanding. A well-established and internationally accepted classification for adenocarcinomas of the esophagogastric junction (AEG) helps to choose the appropriate surgical approach and to make results from different institutions comparable. Distal esophageal adenocarcinomas (AEGI) are distinguished from true cardia carcinomas (AEG II) and subcardiac gastric cancers (AEG III). Substantial advancements in this surgical field during the preceding decades have clearly revealed that individualization of the surgical strategy is the key to successfully approaching these entities. In this review we discuss the surgical management of esophagogastric junction tumors with a tailored surgical strategy.
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Affiliation(s)
- Burkhard H A von Rahden
- Department of Surgery, Technische Universitat Munchen, Ismaningerstr 22, Munchen D-81675, Germany.
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Alexiou C, Khan OA, Black E, Field ML, Onyeaka P, Beggs L, Duffy JP, Beggs DF. Survival after esophageal resection for carcinoma: the importance of the histologic cell type. Ann Thorac Surg 2006; 82:1073-7. [PMID: 16928541 DOI: 10.1016/j.athoracsur.2006.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2005] [Revised: 03/02/2006] [Accepted: 03/07/2006] [Indexed: 01/12/2023]
Abstract
BACKGROUND The significance of tumor cell type on survival after esophageal resection for carcinoma is uncertain. We reviewed our experience in order to compare the outcome in the two main histologic groups. METHODS Between January 1987 and April 2000, 621 patients underwent esophagectomy with curative intention for squamous cell carcinoma or adenocarcinoma. The postoperative outcomes of patients with adenocarcinoma and squamous cell carcinoma were compared. RESULTS Of the cohort, 424 patients had adenocarcinoma (group A) and 197 had squamous cell carcinoma (group B). The commonest approach in group A was a left thoracotomy (67%), while in group B, it was an Ivor Lewis resection (55%) (p < 0.0001). Operative mortality was 3.5% for group A and 8.1% for group B (p = 0.03). Cardiorespiratory complication rate was similar, but anastomotic leaks occurred more frequently in group B (4.2% vs 8.6%, p = 0.04). Patients in group B tended to have earlier pathologic tumor, node, metastasis (pTNM) stage (p = 0.06). Overall, survival was significantly better for group B (p = 0.003). Group B had a significantly better survival than group A in lymph node (LN) negative status (p = 0.01), and a relatively improved survival in LN positive status (p = 0.35). On multivariate analysis, squamous cell subtype (p = 0.034), pTNM stage (p = 0.005), LN status (p = 0.008), and completeness of resection (p = 0.028) were significant predictors of survival. CONCLUSIONS After esophagectomy, patients with squamous cell carcinoma have a poorer perioperative outcome as compared with those with adenocarcinoma. However, in the longer term, squamous cell type appears to confer a significant survival advantage.
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Affiliation(s)
- Christos Alexiou
- Department of Cardiothoracic Surgery, Nottingham City Hospital, Nottingham, United Kingdom
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Wang S, Zhan M, Yin J, Abraham JM, Mori Y, Sato F, Xu Y, Olaru A, Berki AT, Li H, Schulmann K, Kan T, Hamilton JP, Paun B, Yu MM, Jin Z, Cheng Y, Ito T, Mantzur C, Greenwald BD, Meltzer SJ. Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis. Oncogene 2006; 25:3346-56. [PMID: 16449976 DOI: 10.1038/sj.onc.1209357] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.
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Affiliation(s)
- S Wang
- Division of Gastroenterology, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA
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Abstract
GOALS Review recent developments in Barrett's dysplasia including regulatory approval of porfimer sodium photodynamic therapy. BACKGROUND Barrett's esophagus is thought to be the result of long-standing gastroesophageal reflux disease and is known to be the most important risk factor for the development of esophageal adenocarcinoma. The natural history of Barrett's esophagus is not well known, but the annual incidence of invasive adenocarcinoma is estimated to be 0.5% (reported range, 0.2%-2.0%). This represents an increased risk for esophageal cancer of 30 to 60 times higher than normal subjects. As for colorectal cancer, malignant degeneration is Barrett's esophagus is thought to occur through a continuum of histologic stages: metaplasia, dysplasia and neoplasia. Barrett's high-grade dysplasia (formerly referred to as carcinoma in situ) is the histologic stage of disease that immediately precedes the development of invasive carcinoma. CONCLUSIONS Previously, Barrett's high-grade dysplasia patients were routinely referred for esophageal resection surgery based upon the assumption of inevitable progression to cancer, the high rate of undiagnosed synchronous cancers, and few treatment alternatives. Important developments in Barrett's high-grade dysplasia include recent publications regarding the natural history of Barrett's high-grade dysplasia and the regulatory approval for endoscopic ablation therapy using porfimer sodium photodynamic therapy (Photofrin PDT).
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Affiliation(s)
- Herbert C Wolfsen
- Department of Medicine and Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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von Rahden BHA, Feith M, Stein HJ. Carcinoma of the cardia: classification as esophageal or gastric cancer? Int J Colorectal Dis 2005; 20:89-93. [PMID: 15688098 DOI: 10.1007/s00384-004-0646-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/07/2004] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The cardia is the anatomical borderland between the esophagus and stomach. Carcinomas of the cardia are regarded to share features of both, esophageal and gastric cancers. Controversy exists concerning their appropriate classification and whether these tumors comprise--in respect to tumor biology, pathophysiology as well as clinical features--an entirely separate entity. CLASSIFICATION In order to distinguish cardia carcinomas from other adenocarcinomas arising within the vicinity of the esophagogastric junction, a classification system has been introduced from a surgical viewpoint, and is now well established and increasingly used worldwide. According to the topography of the main tumor mass, cardia carcinomas (AEG II) are distinguished from adenocarcinomas of the distal esophagus (AEG I) and subcardiac gastric cancers (AEG III). The tumor-node-metastasis (TNM) staging system by the International Union Against Cancer (UICC) does not provide a separate classification for tumors of the esophagogastric junction. The use of the classification for esophageal or for gastric cancers is recommended, irrespective of the elementary differences in the classification of lymphatic spread implemented herein. DISCUSSION New aspects concerning this controversial debate are discussed based on current insights into the pathogenesis and the cellular origin of these entities. The controversies concerning the classification of cardia carcinomas and the failure of the current esophageal and gastric cancer staging systems to reflect the peculiarities of this entity accurately, present a strong argument in favor of a new classification system.
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Affiliation(s)
- Burkhard H A von Rahden
- Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der TU München, Ismaningerstrasse 22, 81675 Munich, Germany
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von Rahden BHA, Stein HJ, Feith M, Becker K, Siewert JR. Lymphatic Vessel Invasion As a Prognostic Factor in Patients With Primary Resected Adenocarcinomas of the Esophagogastric Junction. J Clin Oncol 2005; 23:874-9. [PMID: 15681533 DOI: 10.1200/jco.2005.12.151] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose To evaluate the value of lymphatic vessel invasion (LVI) as a predictor of survival in patients with primary resected adenocarcinomas of the esophagogastric junction (AEG). Patients and Methods We prospectively evaluated 459 patients undergoing primary surgical resection for tumors of the esophagogastric junction at our institution between 1992 and 2000 (180 adenocarcinomas of the distal esophagus, AEG I; 140 carcinomas of the cardia, AEG II; and 139 subcardial gastric cancers, AEG III). Median follow-up was 36.8 months. The prevalence of LVI was evaluated by two independent pathologists. Univariate and multivariate analysis of prognostic factors was performed. Results The total rate of LVI was 49.9%, with a significant difference between AEG I (38.9%) and AEGII/III (57.0%, P = .0002). Univariate analysis showed a significant correlation between LVI and T category (P < .0001), N category (P < .0001), and resection status (R [residual tumor] category; P < .0001). This was shown for the group of all AEG tumors, as well as for the subgroups AEG I and AEG II/III. On multivariate analysis, LVI was identified as a significant and independent prognostic factor (P = .050) in the population of all patients and in patients with AEG II/III, but not in the subgroup with AEG I. Conclusion These data demonstrate the prognostic significance of LVI in patients with AEG tumors, with marked differences between the subgroups AEG I versus AEG II/III. The lower prevalence and lack of prognostic significance of LVI in AEG I might be explained by inflammation involved in the pathogenesis of this entity.
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Affiliation(s)
- Burkhard H A von Rahden
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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Abstract
Because of the perceived high risk of esophagectomy and the assumed poor long-term results, the role of surgical resection as the mainstay of treatment for localized esophageal cancer is currently being challenged. Early tumors are increasingly approached by endoscopic mucosectomy or mucosal ablation techniques, whereas combined radiochemotherapy without surgery has become the treatment of choice for locally advanced tumors at many institutions. Several recent reports and our experience, however, indicate that surgical resection of esophageal cancer has become a safe procedure and long-term survival rates after surgical resection have improved markedly during the past two decades. A number of factors have been associated with the marked reduction in postoperative mortality and improved long-term survival after surgical resection. They include changes in the epidemiology with an increased rate of adenocarcinoma mostly located distally, patient selection for surgery, improvements in surgical technique and perioperative management, and the use of neoadjuvant treatment protocols. The treatment strategy and extent of the surgical procedure can now be tailored based on histologic tumor type, tumor location, tumor stage, and the general condition of the patient. With an individualized approach, surgical resection of esophageal cancer can predictably offer cure. Surgical resection thus remains the major pillar in the successful treatment of esophageal cancer.
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Stein HJ, von Rahden BHA, Siewert JR. Survival after oesophagectomy for cancer of the oesophagus. Langenbecks Arch Surg 2004; 390:280-5. [PMID: 15252736 DOI: 10.1007/s00423-004-0504-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2004] [Accepted: 04/07/2004] [Indexed: 02/07/2023]
Abstract
BACKGROUND Formerly an inevitably fatal disease, oesophageal cancer today has predictable chances for cure. METHODS The recent literature and authors' own experiences in the surgical management of oesophageal cancer was reviewed to identify factors associated with improved survival after oesophagectomy. RESULTS Currently reported overall 5-year-survival rates are reaching 40% and more in patients who have had an oesophagectomy performed with curative intention. The reasons for improved survival after surgical resection are multifactorial in nature: decreased postoperative mortality and morbidity (due to improved patient selection, surgical technique and perioperative management), the use of tailored surgical strategies (adopted to the histological tumour type, tumour location, stage of disease and the individual patient's risk profile), and multimodality treatment in patients with locally advanced disease. CONCLUSION The prognosis of patients who have had oesophagectomy for oesophageal cancer has markedly improved during the past decades. With improved long-term survival after oesophagectomy, postoperative quality of life gains importance as an additional parameter of outcome after oesophageal cancer surgery.
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Affiliation(s)
- Hubert J Stein
- Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany.
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