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Oesophageal Cancer: A Comprehensive Review

Oesophageal Cancer: A Comprehensive Review

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An essay for the 2012 Undergraduate Awards Competition by Catherine Duane . Originally submitted for BSc. Human Health and Disease at Trinity College Dublin, with lecturer Dr. Nick Kennedy in the category of Medical Sciences
An essay for the 2012 Undergraduate Awards Competition by Catherine Duane . Originally submitted for BSc. Human Health and Disease at Trinity College Dublin, with lecturer Dr. Nick Kennedy in the category of Medical Sciences

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Published by: Undergraduate Awards on Aug 31, 2012
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Oesophageal Cancer: A Comprehensive Review
Oesophageal cancer is an extremely prevalent malignancy in both Ireland andthe United Sates. The increasing incidence of this malignancy in recent yearscoincides with a shift in histological type and tumour location. These twoimportant factors distinguish the primary types of oesophageal cancer;Squamous Cell Carcinoma and Adenocarcinoma.The precise molecular pathogenesis of oesophageal Squamous Cell Carcinomaremains incompletely defined. However recent research implicates the loss of various tumour suppressor genes as an important factor in the development of this disease. Adenocarcinoma of the oesophagus is strongly linked togastroesophageal reflux disease (GORD). Other pathogenic factors involved inoesophageal adenocarcinoma include drugs which relax the gastroesophagealsphincter, and abdominal obesity. A condition called Barrett’s oesophagus,characterised by an abnormal change in the cells of the distal portion of theoesophagus is the typical background to oesophageal adenocarcinomadevelopment.Chromosomal abnormalities are present at early stages of oesophagealadenocarcinoma; in particular the occurrence of p53 mutations. Other potentialgenetic mutations include amplification of c-ERB-B2, cyclin D1, and cyclin Egenes; and allelic loss of the cyclin-dependnt kinase inhibitor p16/INK4a.Inflammation is a contributing factor to the neoplastic progression which occurs inadenocarcinoma of the oesophagus. Recent research demonstrates thatinflammation is a key contributing factor in the development of adenocarcinomaof the oesophagus following the discovery that NF-κb, a transcription factor withcentral pro-inflammatory and anti-apoptotic roles, is present in the oesophagealcells during the advanced stages of the disease.The insidious onset of both oesophageal squamous cell carcinoma andadenocarcinoma means that patients often remain asymptomatic until relativelyadvanced stages of the disease. Ultimately dysphagia, odynophagia andobstruction occur .Impaired nutrition and the effects of the tumour itself mayresult in extreme weight loss.The rich submucosal lymphatic network of the oesophageal region promotes thespread of the tumour away from the primary mass. By the time of diagnosislymphatic involvement is usually quite extensive. Lymphadenopathy, particularlyof Virchow’s node, may be a presenting complaint of advanced disease and isindicative of metastases.It is imperative to devise new treatment strategies for oesophageal cancer inorder to increase the survival rate. A strong link has been discovered betweenVEGF-C and the clinicopathological parameters of the disease. Thus, it is
possible that VEGF-C may be a potential target for antiangiogenic andantilymphangiogenic therapy in the future. This would be a pivotal treatmentstrategy given the rich lymphatic supply to the oesophagus and the advancedmetastatic stage at which this cancer is normally detected. Further explorationinto the use of NF-κb inhibitors, and NSAIDs such as COX-2 inhibitors and Aspirin, may yield promising results.Current treatments for oesophageal cancer yield disappointing results, with apoor prognosis for patients. A strong emphasis must therefore be placed onpreventative measures, by reducing risk factors such as smoking, alcohol intake,and obesity. The emphasis of current research must be placed on devisingpreventative measures to reduce the occurrence of this disease, given the poor success rate of any current treatment strategies.
The oesophagus is a hollow, highly distensible muscular tract which begins at theepiglottis of the pharynx and extends to the gastroesophageal junction.Oesophageal cancer is malignancy of this muscular tube, typically a carcinomaarising from the epithelial lining. The incidence of oesophageal cancer in Irelandhas increased in recent years. Prior to 1995 it was the 13
most common cancer in the country, however the number of new cases diagnosed increased byapproximately 2% per annum during the period 1995-2007.
 A similar trend hasbeen recorded in the United States, where it has been shown that the increasingincidence of oesophageal cancer is coinciding with a shift in histological type andprimary tumour location.
Typically oesophageal malignancies fall into one of twocategories; squamous cell carcinoma (SCC) or adenocarcinoma (AC) accordingto histological type and also tumour location. In recent years AC has become themost prevalent oesophageal malignancy in the United States and WesternEurope, although the incidence of SCC remains higher worldwide. Other raretypes of oesophageal cancer include variants of SCC and non-epithelial tumourslike leiomyosarcoma, malignant melanoma and lymphoma.
Both SCC and AC of the oesophagus show a strong gender bias occurring morefrequently in males.
SCC affects African-Americans more commonly thanCaucasians, while the opposite is true of AC.
Chronic irritation and inflammation of the oesophageal mucosa appears toincrease the risk of developing SC of the oesophagus. It is believed that morethan 90% of all cases in the developed world are attributable to substantialalcohol intake and tobacco use.
SCC may be directly related to lowsocioeconomic status due to deficiency syndromes such as Plummer-Vinsonarising from poor nutrition.  Achalasia, an oesophageal motility disorder may
result in the retention of food in the oesophagus, which is then decomposed bybacteria releasing various chemical irritants.
 Nonepidermolytic palmoplantar keratoderma (tylosis) is the only recognisedfamilial syndrome that predisposes patients to oesophageal SCC. It is a rareautosomal dominant disorder, in which a genetic abnormality occurs atchromosome 17q25. It may confer up to 95% risk of oesophageal SCC inafflicted individuals by the age of 70.
The precise molecular pathogenesis of oesophageal SCC remains incompletelydefined. However it has been shown that the loss of tumour suppressor genesincluding p53 and p16/INK4A is involved.
 SCC begins as a lesion, usually inthe middle third of the oesophagus referred to as squamous dysplasia. Similar lesions occurring at other sites in the body are referred to as intraepithelialneoplasia or carcinoma. The lesion first appears as small, grey-white, plaque-likethickenings which over months to years grow into tumour masses. Such massesmay be polypoid or exophytic and protrude into and obstruct the lumen of theoesophagus. Symptomatic tumours are generally very large at diagnosis andhave already invaded the oesophageal wall.
  AC of the oesophagus is strongly linked to gastroesophageal reflux disease(GORD). Persistent reflux symptoms lead to an eightfold increase in the risk of  AC development.
Up to 10% of AC malignancies may be attributable to drugswhich relax the gastroesophageal sphincter, hence increasing reflux, such asanticholinergic agents, aminophyllines and beta-blockers.
The frequent use of antacids or histamine H
antagonists are also associated with an increased risk.
It has been postulated that the increasing prevalence of obesity in the developedworld is adding to the rising incidence of oesophageal AC.
It is believed thatobesity increases the occurrence of GORD due to an increase in intra-abdominalpressure.
A study published in 2008 suggests that abdominal obesity increasesthe risk of oesophageal AC independent of BMI and that this association was notsignificantly mediated by the presence of GORD symptoms.
The conclusiondrawn from this study suggests that since metabolic products of intra-abdominalfat, such as IGF and leptin are associated with malignancies through pro-neoplastic changes at the cellular level; that it is in fact these compounds whichinfluence cancer development. The metabolic products of intra-abdominal fatmay directly influence AC development or may modify the risk after injury fromother factors such as GORD.
Oesophageal AC typically arises in a background of Barrett’s oesophagus; acondition characterised by an abnormal change in the cells of the distal portion of the oesophagus. Columnar epithelium more typically seen in the stomach or intestine extends proximally from the gastroesophageal junction and replaces thesquamous cell epithelium which normally lines the oesophagus. Chronic GORDis thought to be the main cause of Barrett metaplasia due to acid exposure.

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