User:Anthonyhcole/Adenocarcinoma of the esophagus

World cancer report
"tend to arise in high-resource populations"

"Adenocarcinoma of the oesophagus is a malignant epithelial neoplasm with glandular differentiation arising predominantly from Barrett mucosa and typically encountered in the lower third of the oesophagus."

Etiology
"Oesophageal adenocarcinoma is characterized by a high male-to-female ratio (from 4 to 7), with a higher incidence among Caucasians and among subgroups with a high socioeconomic status [14,15]. The incidence and prevalence of oesophageal adenocarcinoma was reported as rising during the last decades of the 20th century in a number of high-resource countries [14–16]. For example, in the USA, incidence rates for adenocarcinoma have been rising markedly, whereas rates for squamous cell carcinoma are declining steadily. From 1999 to 2008, rates among White men increased substantially (1.8% per year), as among White women (2.1% per year) and Hispanic men (2.8% per year). No significant changes were observed for men or women of other racial/ethnic groups. While rates of oesophageal adenocarcinoma have been increasing among Caucasians in some populations, it is extremely difficult to quantify the rate of increase from analysis of time trends in registry data, due partly to improvements in recording and capturing histology information (decreasing numbers of tumours without histological confirmation) but also because of changes in the assignment of cancers at the gastro-oesophageal junction, from the gastric cardia (or gastric, other/non-specified) to the oesophagus.

"Obesity is a strong risk factor for oesophageal adenocarcinoma, as is gastro-oesophageal reflux disease. The trend of increasing incidence rates of oesophageal adenocarcinoma parallels the growing obesity epidemic and the prevalence of gastro-oesophageal reflux disease [15]. However, in a 2012 study in the USA, incidence rates of oesophageal adenocarcinoma were 7-fold higher among White men than among Black men, despite data indicating that the prevalence of obesity is higher among Black men and women than among White men and women [15].

"The countries with the highest incidence of this tumour type are the United Kingdom, Australia, the Netherlands, and the USA. Relatively lower incidence rates are reported from eastern Europe and Scandinavia. In Latin America, Asia, and Africa, oesophageal adenocarcinoma remains uncommon, but it is possibly also underreported (particularly in Latin America).

"Obesity is a strong risk factor for oesophageal adenocarcinoma, as is gastro-oesophageal reflux disease. The trend of increasing incidence rates of oesophageal adenocarcinoma parallels the growing obesity epidemic and the prevalence of gastro-oesophageal reflux disease [15]. However, in a 2012 study in the USA, incidence rates of oesophageal adenocarcinoma were 7-fold higher among White men than among Black men, despite data indicating that the prevalence of obesity is higher among Black men and women than among White men and women [15].

"The countries with the highest incidence of this tumour type are the United Kingdom, Australia, the Netherlands, and the USA. Relatively lower incidence rates are reported from eastern Europe and Scandinavia. In Latin America, Asia, and Africa, oesophageal adenocarcinoma remains uncommon, but it is possibly also underreported (particularly in Latin America).

"Although familial association has been reported for patients with oesophageal adenocarcinoma, population-based studies show limited influence of familial risk, consistent with the rapid changes in incidence rates observed in many populations over a very short time period. The epidemiological features of adenocarcinoma of the oesophagus and of the oesophago-gastric junction match those of patients with known intestinal metaplasia in the distal oesophagus, i.e. Barrett oesophagus [15]. Barrett oesophagus has been identified as the single most important precursor lesion and risk factor for oesophageal adenocarcinoma, irrespective of the length of the segment with intestinal metaplasia. Intestinal metaplasia of the oesophagus develops when the squamous oesophageal epithelium is replaced by columnar epithelium during the process of healing after repetitive injury, typically associated with gastro-oesophageal reflux disease. Intestinal metaplasia can be detected in the majority of patients with oesophageal adenocarcinoma [17].

Risk of malignant progression in Barrett oesophagus patients
"Barrett oesophagus (BO) is a precursor of oesophageal adenocarcinoma. The magnitude of cancer risk in BO is crucial in determining whether the benefits of screening, surveillance, or treatment of BO outweigh any risks and whether such strategies are cost-effective. The published incidence of malignancy in BO varies widely, from 0 to 35.5 cases per 1000 person-years of risk (pyr) [1]. To date, most studies have been small, and publication bias in favour of studies showing high risks has been demonstrated [2]. Other design issues, such as the inclusion of unrepresentative cohorts of BO patients (e.g. patients from tertiary referral centres), inclusion of those at high risk of progression (e.g. with high-grade dysplasia at baseline), incomplete follow-up of patients, or failure to exclude early incident (most likely prevalent) cancers, have resulted in overestimation of the risks of malignant progression in BO. Differing criteria for diagnosis of BO, for example inclusion of patients without specialized intestinal metaplasia, and differing definitions of malignant progression, for example inclusion/exclusion of incident high-grade dysplasia, have also contributed to the variation in observed rates. The combined risk of oesophageal adenocarcinoma or high-grade dysplasia may provide a better estimate of malignant progression than risk of oesophageal adenocarcinoma alone, although it will overestimate risk as not all patients with high- grade dysplasia would progress to cancer in the absence of therapeutic intervention [3].

"The best estimates of risk of malignant progression in BO are provided by population-based studies with long-term follow-up for a high proportion of patients (excluding those with high-grade dysplasia at baseline) and discounting events occurring soon after diagnosis. Several such studies have recently been published [4–8]. Even in these studies, differing BO definitions, different proportions of patients with low-grade dysplasia at baseline, and differing approaches to, and completeness of, follow-up have resulted in variable estimates of malignant progression. Among patients without low-grade dysplasia at baseline, the incidence of oesophageal adenocarcinoma/high-grade dysplasia ranged from 2.2 per 1000 pyr [4] to 5.2 per 1000 pyr [6,8]; however, the higher estimates were not based on follow-up of all diagnosed cases and may have overestimated risk. Risk of oesophageal adenocarcinoma/high-grade dysplasia was 2–6-fold higher in patients with low-grade dysplasia at baseline than in those without low-grade dysplasia.

"Using currently available data, it is difficult to reach a definite conclusion about the risk of malignant progression in BO, but it is lower than previously thought and, in patients without low- grade dysplasia at baseline, appears to be lower than 5 cases of oesophageal adenocarcinoma/high- grade dysplasia per 1000 pyr.

"A meta-analysis of studies in patients with Barrett oesophagus demonstrated an incidence of progression to adenocarcinoma of about 6.1 per 1000 person-years, which reduced to 3.9 per 1000 person-years when only high-quality studies were considered [18], corresponding to a lifetime risk of about 10% in these patients. However, these results may be overestimations that reflect various types of bias in the studies. More recently, an Irish study reported a rate of 3.8 per 1000 person-years [19], whereas a Danish study showed a considerably lower progression rate of only 0.12% per year [20], although obesity is far less prevalent in the Danish population than in the United States or Irish population (see “Risk of malignant progression in Barrett oesophagus patients”).

"Chronic gastro-oesophageal reflux disease is the usual source of mucosal injury and also provides an abnormal environment during the healing process that predisposes to intestinal metaplasia and adenocarcinoma. In a large Swedish study, individuals with long-standing and severe gastro- oesophageal reflux disease symptoms had a 40-fold increased risk of oesophageal adenocarcinoma [21]. Both experimental and clinical data indicate that combined oesophageal exposure to both gastric acid and duodenal contents (bile acids and pancreatic enzymes) appears to be more carcinogenic than exposure to only gastric juice or duodenal contents. An association between alcohol consumption and oesophageal adenocarcinoma has not been well established. A reduced risk of oesophageal adenocarcinoma is associated with Helicobacter pylori infection, and particularly H. pylori strains with the CagA protein. A protective effect has been suggested after the use of non-steroidal anti- inflammatory drugs, but not all studies have supported such data.

Pathology and genetics
"Pathology and genetics Adenocarcinoma in Barrett oesophagus develops through a progressive sequence of morphologically identifiable premalignant lesions termed “dysplasia”. Dysplasia is diagnosed by the presence and degree of cytological and architectural atypia [22]. Low-grade dysplasia shows pits with relatively preserved architecture, or minimal distortion, containing cells with atypical nuclei limited to the basal portion of the cell cytoplasm. High-grade dysplasia is diagnosed by the presence of marked cytological abnormalities and/or significant architectural complexity of the glands (Fig. 5.3.4A). Cytological abnormalities include nuclear pleomorphism and loss of polarity, irregularity of nuclear contour, and increased nuclear-to-cytoplasmic ratio. Architectural abnormalities of high-grade changes include crypt budding, branching, marked crowding, and, rarely, a cribriform growth pattern.

"Intramucosal adenocarcinoma (invasion into the lamina propria; T1a) show single cells or small clusters of compact back-to-back glands within the lamina propria, a cribriform or solid pattern of growth with expansion and distortion of the adjacent crypts, and a highly distorted/irregular glandular proliferation not explained by the presence of preexisting glands. The presence of necrosis and/or desmoplasia is evidence in favour of adenocarcinomas as well, although these features are rarely present in carcinomas limited to the mucosa.

"Oesophageal adenocarcinomas are typically papillary and/or tubular. Most cases are of the intestinal type in the Laurén classification (Fig. 5.3.4B), whereas some are of the diffuse type. Multiple genetic alterations are involved in the development and progression of Barrett oesophagus to oesophageal adenocarcinoma, encompassing tumour suppressor genes, oncogenes, growth factor receptors, or enzymes that play important roles in diverse cellular functions such as cell-cycle control, apoptosis, cell signalling, cell adhesion and genetic stability, signal transduction, and DNA repair. Gains in the region of 8q (region of c-myc) and 20q, and losses at 3p (FHIT), 4q, 5q (APC) and 18q (SMAD4, DCC) have all been reported, with an increasing number of chromosomal alterations in the sequence from metaplasia to intraepithelial neoplasia to carcinoma. Gene silencing by promoter hypermethylation has been demonstrated frequently for the CDH1 gene (which encodes E-cadherin) and the APC, p16, MGMT, and HPP1 genes. Disorders of ARID are also noted.

"Exome and whole-genome sequencing of 149 and 15 oesophageal adenocarcinomas has been recently reported [23]. A mutational signature was defined by a high prevalence of A → C transversions at AA dinucleotides. Of 26 significantly mutated genes, TP53, CDKN2, SMAD4, ARID4, and PIK3CA had been implicated previously. The new significantly mutated genes included chromatin modifying factors and candidate contributors SPG20, TLR4, ELMO1, and DOCK2 (Fig. 5.3.5). Functional analysis of the relevant mutations in ELMO1 identified increased cellular invasion."

Prospects
"Novel endoscopic techniques for early detection and treatment of oesophageal adenocarcinoma offer promise. Ablation therapy for high-grade dysplasia (the strongest risk factor for adenocarcinoma) is probably cost-effective [24]. Ideal strategies for population-based screening in high-risk patients remain poorly established and inconsistent.

"A recent review [25] determined that endoscopic screening is invasive, costly, and error-prone owing to sampling bias and the subjective diagnosis of dysplasia. Non-endoscopic cell sampling methods (Fig. 5.3.6) are less invasive and more cost-effective than endoscopy, but the sensitivity and specificity of cytological assessment of atypia have been disappointing. The use of biomarkers to analyse samples collected using pan-oesophageal cell collection devices may improve diagnostic accuracy."

"The inflammatory response to gastric acid reflux in Barrett disease may be responsible for the increased incidence of oesophageal cancer."

"Epidemiological studies have provided convincing evidence that obesity increases the risk of cancers of the oesophagus (adenocarcinoma)"

"The mechanisms through which obesity increases cancer risk are only partially understood but appear to vary between different cancer sites. For adenocarcinoma of the oesophagus, the increase in cancer risk probably involves an increase in the prevalence of chronic acid reflux from the stomach into the oesophagus, which damages the oesophageal epithelium."

Inflammation and cancer
"A reduction in the prevalence of H. pylori in Caucasian individuals in the USA and other areas of the world has been paralleled by a dramatic decline in stomach cancer incidence, although accompanied by increased incidence of oesophageal adenocarcinoma, which may be associated with concurrent increases in obesity and gastro-oesophageal reflux or with bacterial dysbiosis in the upper digestive tract in the absence of H. pylori [6]."

Alcohol consumption
"...reduced consumption of alcohol will contribute to lower incidences of cancers of the oral cavity, oesophagus, liver, female breast, and some other sites."