The Etiology And Epidemiology Of Esophageal Adenocarcinoma

Adenocarcinoma (EAC) occurs in the distal part of esophagus and has a strongest link to gastro/esophageal reflux disease (GERD).Prolonged acid reflux without treatment can progress to cause damage of the layer of the lower part of esophagus , and the normal layer(stratified squamous) will replaced by abnormal columnar epithelium layer. Globally ESC affects around 450 thousands of individual and the incidence has been increased so rapid. Currently, ESC is categorized as number eighth most common incident cancer worldwide, because it’s very aggressive malignancy and has poor prognosis.

Barrett’s esophagus(BE) and gastro-esophageal reflux Disease (GRED) - Major esophageal adenocarcinoma risk factors are GERD and Barrett esophagus. And the link between GERD and esophageal adenocarcinoma is Barrett’s esophagus (BE).

As we know the acid reflux contain some contents that have a direct effect on mucosa of the lower part of the esophagus, those contents like bile acid and enzyme which come from the duodenum make irritation on that part of esophagus. The frequency of gastric reflux and after long time plays a main role to make injury on the squamous epithelium of esophagus. Normally this injury due to the reflux heal by the regeneration of squamous epithelium, but actually healing occur by a metaplastic progression in which squamous convert to columnar epithelium which is abnormal layer. That change of the layers known as Barrett’s esophagus. Clinically barretts esophagus can occur due to some conditions like Achalasia, scleroderma, duodenal ulcer (particularly active ulcer), previous gastric surgery such as esophageal duodenal anastomosis and Crohn's disease.

Study by Spechler et al (1983) for 25 patients complain of GRED, those patients already had esophageal stricture but they didn’t have barretts esophagus. They demonstrated that: 11 patients of the 25 patients after 1 to 4 years developed BE after the diagnosis. That is mean GRED was the cause of BE rather than the result.

Regarding the association between gastric reflux every week and risk of esophageal adenocarcinoma there are some studies confirmed this association. In the Swedish case-control study by Lagergren et al (1999) they found there was a relationship between reflux every week and risk of adenocarcinoma. Also found reflux more than 3 times per week associated with highly odd ratio compared to no reflux.

In addition to previous study also there is study by Farrow et al (2000) demonstrated that reflux every day increased the risk of esophageal adenocarcinoma about 5 folds. Also study by chow et al (1995) confirmed that association, and they found the risk increased in range from 2 to 4 folds. Kim et al (1997) on their study estimated that 8 to 14 % of patients had chronic GRED progressed to adeno eosophgeal cancer. After all of above studies we can consider GRED/BE are main risk factor of oesophgeal adenocarcinoma.

Obesity

According to recent study Lauby-Secretan et al (2016) there was association between obesity and Barrett esophagus and esophageal adenocarcinoma. After case control and cohort studies they found that people who had BMI in range 25 to 30, their relative risk for EAC was 1.71, and was 2.34 for BMI more than 30.They revealed people with high BMI have 7.6 fold risk to develop EAC.

The obesity can lead to GRED by 3 ways either due to increased gastresophageal sphincter gradient, increasing in intra-abdominal pressure and increased incidence of hiatus hernia in obesity according to Mercer et al (1987), El-Serag et al (2006) and Pandolfino et al (2006) respectively.

Also interesting study by Edelstein et al (2007) they brought people new diagnosed with BE and compared with matched population controls, that case group included any visible BE, after abdominal measurement for any person, they found abdominal obesity play important role in developing BE. They found the risk of BE was associated with (waist/hip) ratio more than BMI.

Study by Hoyo et all (2012) estimated that Obesity is a clear risk for EAC. Range of BMI 30–34.9 is increasing the risk of EAC like 2.39-fold, compared to who has a BMI less than 25.

Lower esophageal sphincter relaxing drugs

Sweden study by Lagergren et al (1999), they studied 189 EAC (they were recently diagnosed), 262 adenocarcinoma of gastric cardia and 167 SCC. And they compared them with 820 normal people as control. Groups of drugs that were introduced before the incidence of esophageal adenocarcinoma started increasing included: nitroglycerins/aminophylline/β receptor agonists/anticholinergics and benzodiazepines. They estimated the incidence rate ratio by using multivariate logistic regression from case–control data. They reached to the following result :-The incidence was high for those who used the LES relaxing medications every day and more than 5 years compared with people who had not used.- All kinds of drug increased the risk, but anticholinergic drugs had strong association.- 10% of ESC happen in the people intake LES relaxing drug long time.- No association between SCC and cardiac adenocarcinoma with these drugs.

Smoking

Same study for Anderson et al (2007) also found there was strong relationship between smoker and even ex-smoker with EAC. Another study by Cook et al (2010) found that stop smoking for a long time had associaton with a decreasing potential risk of adenocarcinoma.

Another study by Butorin et al (2013) concluded that Continue smoking for more than 10 years at an average of 20 times a day had a strong association with increasing risk of BE. In Netherlands there is another a larger cohort study by Stevens et al (2011), they started their study in 1986 and continued sixteen years. That study included about 120 thousand and 852 males and females, ages around 55 – 69 years. After 16 years follow up they found smoking increased BE risk.

Helicobacter pylori

Some studies found there was association between the presence of H.pylori infection and decreased risk of development of esophageal adenocarcinoma. Let me start with first study by Vaezi et al (2000), they did their study on 251 patients (control / GRED without anything else /short – long segment BE), and all of patients were underwent endscopy, they found that cagA+ H pylori (the cagA+ strain has the most frequent association) more prominent in control 44% of 25 patients and,36% of 36 patients had GRED, 20% of 10 patients had short_segment BE, and 0% had a long segment BE.

Also another study by de Martel et al (2005) concluded that: lack of H.pylori infection increase the malignancy chance of esophagus especially EAC.

Diet

Case control study by Thompson et al (2009) compared the vegetable and fruit intakes of two groups, first was patients diagnosed with BE and intakes vegetables and fruiets, and group controls from the pupbic community. they estimated that eating food rich of fruits, vegetables and fiber frequently decreasing the risk of BE.

Another risk factors

Recently In a cohort study of patients with BE by Nguyen et al (2010), they tried to study and test if there is any link between intake bisphosphonate drugs orally and developing esophageal adenocarcinoma in those patient had BE.11 823 patients with BE, versus 1 1 6 cases and 6 9 6 controls. 97% were males. The majority of them (cases and control) had minimally one filled PPI drug (95 vs. 9 4%, P = 0.5). Filled with bisphosphonate drug were a little (1.7 vs. 1.9%) and weren’t related with EAC, the incidence ratio was 0. 92 (95% CI, 0. 21–4. 15).

Evidence: the incidence of esophagi adenocarcinoma rapidly increased in Western cultures especially the manufacturing countries, such as European countries, Australia and New Zeeland, nearly 50% of all cases occur in west Europe and North America. Previously, in the United States SCC was the most widespread and the dominant type of esophageal cancer in general, and EAC accounted about 5% of populations, but in 1990 EAC appears to be risen quickly and has become the most prevalent type.

In 2014, there were just about 18 thousands incident of esophageal cancers in the USA, 59.9% of which were EAC. EAC is less frequent and not common in Asia and Africa, but in China due it’s a large number of population it has approximately eighteen percent of all incident cases worldwide.

Prevalence and Incidence of BE and GRED: Barret's Esophagus incidence has been steadily increasing over the last few decades according to records worldwide. Probably this is due to the current developments in the screening methods and investigation tools. Corley et al (2009).Barrett’s esophagus mainly affects older adults in the developed countries. It is difficult to determine the accurate prevalence in living adult, and the reason is people with BE are usually asymptomatic and do not look for care or even routine investigations. But a Swedish study by Ronkanen et al (2005) evaluated the prevalence of BE by perform endoscopy on approximately 1000 randomly selections of adult. They found BE in 16 (1.6%) of the individuals. This study also showed that the prevalence of Barrett’s esophagus was 2.3% in those who had acid reflux symptoms.

Study by Lagergren et al (1999) signified that the risk of BE was about eight fold more in patients with recurrent acid reflux symptoms than those without acid reflux symptoms. Barrett’s esophagus develop to EAC in a small proportion of people, at rate range from 0.12% per year to 0.60% per year according to Hvid-Jensen (2011).

Another study by Rubenstein, J.H. and Taylor (2010) estimated that GERD symptoms every week increase the possibility of EAC like 5 fold. Patients with prolonged, recurrent symptoms or that symptoms occur at night have a highly risk. However no associations between the severity of the symptoms increasing of risk of EAC. Study by Rubenstein (2014) found that It is possible that chronic acid reflux could endorse EAC without even causing significant symptoms before patients present with malignancy. It is now clear that most EAC develop from BE, which are derived from gastresophageal reflux disease (GERD). In Western countries, GERD is a commonly seen clinical entity, with >30% of the general population experiencing its symptoms at least once every month. About 10% GERD patients will finally develop BE.

The risk of developing esophageal adenocarcinoma from known BE is estimated to be 0.5% per patient year.. Altorki et al (1997)Sex- and age-related demographics: Kramer, Fischbach and Richardson et al (2013), showed some important information in their study like the incidence of Barret’s esophagus to be higher in Caucasians compared with Hispanics and. Their study found that 80.6% of those who had Barrett’s esophagus were White.

Based on study of Ford et al (2005) found that Caucasians having significantly higher prevalence as compared to Asian or Afro-Asian. Another a retrospective study by Van Blankenstein et al (2005) They reviewed the medical records of patients who were underwent endoscopy, and also their histological biopsies results, they found that the developing of BT in men happened early up to 20 years before women, and the ratio was 4:1 male.

Conclusion

There are a numerous of risk factors have a direct affection and association to cause BE, and another risk factor can cause a progression to esophagus adenocarcinoma as a complication. We notice also according the previous studies, the differentiations in incidence and prevalence around the world based on some factors like a gender, the color and even multiple lifestyle (smoking or obesity as examples).