In general the oesophageal cancer related to different risk factors like alcohol, tobacco, age , obesity, , hot beverages and Barrett,s>

The inproper use of PPI  may play a role in changing of PH and  accelerate pathological changes  and lead to increase esophageal ca.

Thank you Gamal,

As you mentioned changes in many risk factors might be responsible for the rise of oesophageal adnocarcinoma (OAD). The incidence rise in this question is for adenocarcinoma, as we do not see such a rise in oesophageal SCC globally.

The main risk factor for OAD are GORD, obesity,  male gender (we cant do anything for this!), hiatus hernia and smoking. Alcohol is a risk factor for OSCC rather than OAD. So, obviously we would expect a rise in one or more risk factors mentioned above, but what evidence we have for those rises?

Is H Pylori eradication causing reflux esophagitis and then adenocarcinoma (GE junctional) ?? Really I want to know...

Obesity , mainly trunkal obesity epidemic have resulted in rising incidence of esophageal adenocarcinoma. 

Thank you Amitava,

H.pylori infection is a well-established protective factor for GORD,including symptomatic reflux and reflux oesophagitis. Also, the chance of OAD in H.pylori negative people is higher than H.pylori positive subjects. But, I do not expect to see significant difference between risk of OAD before and after H.pylori eradication, because long-term effects of H.pylori infection will not regress within months and years after eradication.

What i know H.pylori is not incriminated in pathogenesis of GERD or GORD, but how can infection with H.pylori be protective against GERD?

You are right Erwa, H.pylori infection is not a risk factor for GORD!

It protects us against GORD through induction of chronic atrophic gastritis and chronic inflammation involving mainly gastric body mucosa. There are few other possible mechanisms for this protection as well but not very clear evidence for them.

Personally I believe the interaction of visceral obesity and development/progression of BE to EAC is poorly understood and probably more relevant to the increase rates of EAC we have seen over the last three decades (just plot the increase in obesity since the 1970s besides the increase in EAC...they're very similar curves!).

The metabolic activity of visceral fat may well be a reason why BE, once established, is more likely to progress to through dysplasia to cancer in obese patients. This goes beyond the common mechanistic thinking, that visceral obesity simply leads to more GERD. Some good exploratory studies on this influence of visceral fat on the development of EAC can be found from JV Reynolds' group. Further, with regards to "risk factors" for BE/EAC, David C. Whiteman has published some more recent studies linking the use of tobacco, alcohol and obesity to the development of these aforementioned ailments. However my personal caveat with all observational data such as these is that the "symptom" or "variable" analysed as a risk-factor may serve more as a surrogate than as a true causative factor; decomposing the relationship is horrendously difficult. Further, a totally under-researched area is the influence of type of food consumed on EAC development. Diets have changed substantially over the past three decades, which in turn have also been made partially responsible for the increase in obesity. Thus, why can it not be, that the distal esophagus is not also influenced by the stomach content beyond acid and bile salts?

Dear Oliver,

You have mentioned a very good point in the pathogenesis of OAD. Obesity is very important player in the story. Central obesity can increase prevalence of GORD, Barrettes and OAD, so all steps in the OAD cascade are related to the obesity.

The obesity can deliver its effect by two main mechanisms (amongst others!): biological and mechanical. We have investigated the latter extensively, here are examples:

1.Gut. 2012 Mar;61:337-43., 2) Gastroenterology. 2013 Oct;145:730-9. and 3) Gut. 2014 Jul;63:1053-60. All of studies try to explore the long-term injuries to GO junctional area through mechanical pathways, but we are not rejecting biological effects of visceral fat tissue which is almost always a source of inflammation.

But interestingly epidemiological studies indicate that obesity can only explain 6.5% of the rise in incidence of oesophageal adenocarcinoma (Cancer Epidemiol Biomarkers Prev. 2011 Nov;20:2450-6). Moreover, obesity does not explain the geographical variations in the rising incidence of the cancer (Am J Gastroenterol. 2014 Mar;109:336-43).

OAC is rising in developed countries as studies indicate but the same may not be true in other parts of the world e.g. in India and other Asian cuoutries mostly the incidence is stable over the years except the westernised countries like Japan. This definitely points towards some sociocultural influences like food and lifestyle habits. As is well known daily dietary variation have increased tremendously all over the world as cultures from different parts of the world mix. Smoking and alcohol consumption is on the increase. Obesity and H.pylori eradication are definite factors. A small proportion may also be attributed to early and better detection methods at endoscopy

Thank you Gautam,

Obviously the magnitude of the rise in incidence of OAD is not similar all over the world, and as you pointed out,  it is very low or nil in some populations. It is not clear the lack of such rise related to different combinations of risk/protective factors or it is a host characteristic. Smoking rate is falling in most of areas with significant rising incidence of OAD, so it is not responsible for the rise. Gradual disappearance of H.pylori infection during last decades seems to be a major player.

Mohammed thank you for your comments and also for the publications which I greatly appreciate! Just a brief "correction" to your last statement. If I'm not mistaken smoking rates are only decreasing in the western world, whereas in the arabic and asian world smoking is rising, due to increase of wealth and smoking as such being regarded as a "status symbol". Equally the consumption of alcohol has become more "prevalent" in eastern populations...but overall I do agree with you that in comparison to SCC the link between OAD and smoking is less strong. Perhaps with diets changing and with obesity rising in eastern cultures (a major issue in india/china) we'll see an increase of OAD too - but perhaps with a 10-20 year lag?

I think esophageal adenocarcinoma is rising because of  changing human life style , for example we see that eating fast food ,drinking coke and immobility  are common habits that directly increase risk of acid reflux and leading to reflux esophagitis  and esophageal adenocarcinoma .

Thank you very much Farahnaz,

Certainly, oesophageal acid exposure is a major player, as you mentioned.

We should bear in mind that this acid exposure would not be equivalent to classic acid reflux, which is measurable through standard pH-metry catheter with a sensor typically placed at 5 cm proximal to LOS. Most people have oesophageal acid exposure limited to very short distance within LOS which has been called "Intra-sphincteric Reflux" by our team (Gastroenterology. 2013 Oct;145:730-9.). These people may develop typical reflux oesophagitis in future, or the abnormality may remains silent, but will produce a range of histological changes we believe predispose subjects to columnar metaplasia, dysplasia and cancer.

If we assume the above phenomenon is responsible for carcinogenesis (at least in part) why it is rising, may be it is related to changes in the life style, as you pointed well. We know there are huge changes in our diet and life style during last 4-5 decades, but it is very hard to select and concentrate on a set of specific factors to investigate.

So the question from you and other experts is what sort of environmental and life style factors should be prioritised for further investigations.

In addition to these reasons, I think because our mind has changed in term of the locations of tumor, which is esophageal cancer or cardiac gastric cancer.

Yes Binh, there were always some issues on cancer classification.

The main problem was focused on cardia cancer in few studies, for example re-analysis of Swedish cancer Registry data suggested that true cardia (suppose) cancer incidence could be up to 45% higher or 15% lower than that reported in the Cancer Registry (J Natl Cancer Inst. 1999;91:786-90).

In other example from Japan, authors tried to explain rising incidence of cardia cancer, while there was no evidence of parallel rise in incidence of oesophageal adenocarcinoma and they suggest probability of artefacts and/or coding preferences for gastro-oesophageal junction tumours (Eur J Gastroenterol Hepatol. 2002;14:107-13).

The nature of miss-classification of cardia cancer as gastric or oesophageal comes from fact that cancers currently we are classify as cardia cancer are in very small anatomic area between two main compartments of stomach and oesophagus, often differentiation of origin is hard or impossible and the has very little clinical value when the tumour is well grown.

Several years ago we proposed that these tumours we call them cardia cancer, are aetiologically composed of two distinct tumours, gastric or oesophageal. We showed some evidences for our hypothesis by exploring cardia cancers in two Norwegian and Iranian populations. You can see the details of findings in (Gut. 2007;56:918-25) and (Gut. 2008;57:298-305) if interested.

My 2 cents-

1. We are not undertreating heartburn or distal esophageal acid exposure-  20-30 million Americans alone are on ppi meds. 

2. The final link between Barrett's esophagus and esophageal adenocarcinoma is poorly understood.  But look at a the recent Danish study with nearly 10,000 patients with Barrett's and the use of ppis was an independent risk factor for developing esopageal adenocarcinoma. Aliment Pharmacol Ther. 2014 May;39(9):984-91. doi: 10.1111/apt.12693. Epub 2014 Mar 11.

3.  The incidence is of esophageal adenocarcinoma has risen 600% since mid 1970s and if you plot this rise in incidence vs H pylori eradication and H2 blocker/PPI use it is very scary. 

Lots of good areas for ongoing and future research.

Francis,

Thanks for the link to the interesting article by Hvid-Jensen. I rarely like making a "big call" on papers' methodology, partly because I first need to commend the authors on trying to analyze an extremely difficult topic. But a bit of an issue is that they're looking at the risk of developing HGD/OAC over an approximately 10 year period, but did not really acount for the time-variable in their analyses. They performed logistic regression, which when looking at "time-series" has some issues, but this is most likely due to the fact, that they did not have the dates of a) diagnosis of BE/LGD and b) diagnosis of HGD/OAC (a common registry-data issue). Nevertheless this is a problem, because its only taking a "snap-shot" of the study cohort and not taking into account the dynamic changes that occur over time. Accelerated failure time models or cox-proportional hazards modelling would seem to be a more appropriate choice in my personal opinion, but it may not have been possible, because the time-variable was not available. However, the confidence interval estimates aren't too bad, so hopefully this means, that their modelling isn't too inaccurate.

But the biggest issue that remains in the study is adjusting for the variable "low-grade dysplasia". We know that LGD is a diagnosis that is a) completely arbitrary, b) can seldomly be replicated (even by the same pathologist) and c) if accurately detected actually is a disease that has a higher likelihood of progressing to HGD or OAC, than we originally were led to believe. Thus, it must be hypothesized, that in the study by Hvid-Jensen, where they are linking PPI use to a higher risk of OAC, they are in fact not accurately accounting for the possibility, that some patients in their controls didn't even have proper low-grade dysplasia, thus leading to the conclusion that PPIs may pose a risk for the development of OAC. Related to this topic of LGD classification issues is this article by Bergman and colleagues:

http://www.ncbi.nlm.nih.gov/pubmed/25034523

Now don't get me wrong, I'm no fan of PPIs and I don't think that they do a particularly good job in preventing cancer progression etc, its just I'm very careful at interpreting a 600% fold increase in OAC incidence as potentially caused by the use of PPI. PPIs are prescribed because of the clinical picture "reflux" (whatever that may be) and thus, the PPI just serves as a surrogate for other underlying issues, which we are currently not able to account for.

Thanks for your comments.  I agree that it is multifactorial and again think that many will make careers out of studying potential links.  I do know this- the medical community has taken a single approach to treating all things upper GI.  Eradicate H. pylori and place patients on ppi therapy. Much of the Western world walks around with an altered GI physiology.  When it comes to GERD, its symptoms and predominant treatment we have been quick to treat without recognizing that there is the law of unintended consequences.  I am only suggesting that the increase in OAC may be one of these consequences.  Time will tell.  Great thread by the way.

Speaking for The Netherlands (based on figures of the Dutch Cancer Registry www.iknl.nl) a bit more down to earth 'methodological' explanation:

Since 1989, the age standardized incidence (ESR) of esophageal cancer is rising at the same speed as that of stomach cancer is decreasing. Early commentaries explained these trends by all kinds of ingenious physiological and behavioral changes. A more  practical and equally plausible explanation is that more (proximal) stomach cancers, considered as inoperable and incurable, have increasingly become diagnosed as (distal) esophageal cancers, which are treated more aggressively with curative intention. Simply a matter of classifying and treating the same cancer differently.

Dear Francis and Lucas, 

Many thanks for your thoughts, of course every medical intervention has own consequences and great effort go to explore safer ways of treating diseases. In this case careless management of upper GI disease, particularly H.pylori infection in one of the important players.

By the way, Lucas can you tell us what is the main impact of rising OAD incidence on the surgical intervention of upper GI cancers during last two decades?

increase in the incidence of esophageal adenocarcinoma, for which the most common predisposing factor is gastroesophageal reflux disease (GERD) a condition that causes stomach acid to spill into the swallowing pipe, or esophagus and   may be related to the larger number of people who are obese , . Obesity  plays a role in the development of GERD, making those who are very overweight even more vulnerable to developing adenocarcinoma.  GERD is a cancer risk factor because when stomach acid comes into contact with the esophagus, it can damage it and can cause a condition called Barrett’s esophagus, which can then lead to adenocarcinoma.

@ Mohammed,

I believe lucas meant, that there have been some very significant paradigm changes with regards to the definition of "gastric" and "esophageal" cancers in the last 30 years too!

The Siewert classification (SC) of junctional cancers may indeed be responsible for this.

Whereas pre-dissemination of the SC, Type III cancers may have been classified as gastric, some centres may have adopted the general term "distal esophageal" CA to  type II & III after adopting the SC, although III should most likely be regarded as a proximal gastric cancer, which grows cranially.

Type II is infact often also classified as "esophageal" although it is not clear what type of cancer this actually (most likely this is "true" cardiac cancer), and type I is actually classic distal EAC.

Thus, through more refined classificaiton and the adoption of misclassification strategies we may also be seeing a rise in "incidence", whereas this "rise" may actually simply be inflated my wrong terminology.

Personally I believe it is a combination of all of the above, but in summary probably due to:

• More obesity (whatever reasons that may have, but please lets not forget the diet!)
• More reflux
• Classification issues

Oliver Fisher gave a formally more correct description of 'classification issues' than I did. And of course, other factors (obesity, reflux) may also have contributed to the rising incidence of adenocarcinoma of the esophagus.

Dear Friends

I think we had great discussion, with lots of new ideas in 23 conversions.

As I understand from your points, all agree:

1. We have faced with very sharp rise in the OAD incidence during last decades.

2. Chronologically, the rise has coincidence with huge changes in lifestyle and diet.

3. The changes in the main risk factors of OAD including GORD and obesity are partly responsible for the rise in OAD, the magnitude of effect is not clear.

4. The issue of misclassification should be addressed and evaluated properly.

5. Decreasing prevalence of H.pylori and atrophic gastritis in global level is a potential contributor to the rise in OAD.

6. There is a room for other unknown risk factors contributing to the rise.

I think  our discussion has produced lots of new questions, which is an indicator of a successful scientific debate. For example, if we think there are strong evidence for association of OAD with GORD, what evidence we have for such a sharp rise in the prevalence of GORD in different populations and how much contribution we expect to see from the rise in GORD?

I am sure others will produce many novel questions to drive new insight and research in OAD in future.

Thank you all for your time

Dear Colleagues,

An additional hypothesis that we should consider is the effect of H.pylori eradication on gastric motility. At our institution, we are working on the concept that eradication of H.pylori leads to gastroparesis that may in turn increase the esophageal reflux. 

Based on this concept, we may be treating patients with acid reducers for longer than they need. The real treatment should be to "reprogram the gastric motility with pulse therapy using Erythromycin as we have published"

We estimate at almost 50% of patients with so called "idiopathic gastroparesis" may actually have Post H.pylori Gastroparesis ( PHPG). We recommend a Gastric Emptying Study for patients who have dyspepsia after the eradication of h.pylori, generally after 12 weeks post eradication.

Please let me know if members of this group have similar findings.

Thank you.

Dear Zamir,

Many thanks for your contribution.The concept of post eradication gastroparesis is interesting and may have some role in OAD carcinogenesis due to LOS dysfunction , particularly in patients who capable to produce more acid after gastric mucosa recovery. 

One question here is what is the situation in subjects naive for H.pylori infection, as this concept can apply to those with H.pylori infection in the past and then their infection has been eradicated. Do we have any evidence for some degrees of  "Gastroparesis" in H.pylori naive versus H.pylori infected people?

@zamir I'm intrigued by this concept. Do you believe this is caused by the medication used for eradication or by an interaction of HP with the gastric mucosa/muscularis? I would second Mohammed's question, that it would be very good to know what HP-negative (and thus never-infected) patients' gastic motility looks like vs. HP+ and HP-eradicated patients...

Dear Mohammad and Oliver,

Thank you for your responses. In our experience, fewer patients that are HP negative have gastroparesis when compared to those with chronic HP infection followed by eradication.

When patient with current HP infection were studied for gastroparesis, their Gastric motility was found to be normal. This probably occurs due to an induction of Ghrelin hormone in these patients. Once the HP is eradicated and the gastric emptying is measured after 3 months, we observe a significant number of patients with delayed gastric emptying. This would also explain the increase in GERD symptoms in patients post HP eradication. We are currently starting a study to measure the Ghrelin levels in patients with HP and post eradication

A few demographic characteristics of patients that have delayed gastric emptying post eradication include: Female gender, age less than 50, concomitant IBS.

We have also noted that acute HP, less than 3 month duration, when eradication does not lead to post h.pylori gastroparesis(PHPG), possibly because the Ghrelin does not get induced in these patients.

I appreciate your comments on this concept, since this will carve out a large portion of patients with "idiopathic gastroparesis" who can be treated with pulse therapy and their gastric motility can be restored instead of keep them on prolonged PPI therapy with its adverse effects. 

Thank you

Dear Mohammed,

Thank you for your reply.

Just out of interest: isn't the rise in ghrelin triggered by the ppi therapy that is a part of the treatment for HP gastritis?

And may I ask what your control groups are and how "normal gastric motility" is defined? All of these factors are extremely important factors to know...

Thanks.

O.

Dear Oliver,

To my knowledge, PPI therapy does not increase Ghrelin levels, but do increase Gastrin levels.

Our control groups are HP negative patients without clinical signs of Dyspepsia based on a Dyspepsia score.

Regarding the Gastric Emptying Study, Normal is when the T1/2 is 45mins to 95mins after a solid food bolus. We have further graded gastroparesis as Grade 1, T1/2 95mins to 120mins, Grade 2, T1/2 120mins to 180mins and Grade 3 T1/2 more than 180mins.

We welcome your comments. Thank you

ZB

Dear  Zamir,

First, apologies that I replied to you as Mohammed before.

This is truely very interesting data. May I ask how big the sample size was? The correlation of gastrin levels with PPI use is what triggered my question to you, as I too am not aware of any correlation between the both, thus it will be very interesting to see how your future results pan out with regards to this question! Have you found that patients with Grade 1/2 gastroparesis also tend to have higher dyspepsia scores (and or lower pH-metry values)  compared to those who are asymptomatic following eradication?

Have you published this data yet? Because, as you point out, I believe it may provide very valuable information on the link between what we have found with HP eradication and risk increase for BE.

Nice work!

O.

Dear Oliver,

Thank you very much for your kind comments.  Our sample size was not very large considering the prevalence of HP, we have so far studied 150 patients. We are preparing to publish the data, an abstract describing this concept has been published.

With reference to Grade 1/2 gastroparesis, these patients are symptomatic and do have a higher Dyspepsia score compared to patient with patient with T 1/2 in the normal range.

We are also very excited about this data and as you mentioned may answer the "root cause" of the increased incidence of GERD, BE and ultimately esophageal andenocarcinoma.

Also what is more interesting is that the Post Helicobacter Pylori Gastroparesis(PHPG) may be reversible with pulse therapy using erythromycin or a prokinetic agent.

More to come! Thanks.

Zamir

Dear Zamir,

For a prelim study / hypothesis generating study 150 patients is not small! I think that's a very decent ss for this type of data, as it shows, that there is definitely "something out there". Congrats!

And that you don't simply provide a causal observation but also a possible treatment is also great!

I look forward to reading more about this!

Cheers,

O.

The rising of adenocarcinoma of oesphygous is more common in westren world. It has been connected in many studies with type of diet in wetren world. As Olivier mentioned to you maybe with the rising of obesity and changing in diet we will see adenocarcinoma raise in countries were we used to see SCC more common. However I doubt that will happen with the increase in socioeconomic status. Moreover and based on my observation oesphygeal cancer is more connected with occupation.

Completely agree. The obesity epidemic, western lifestyle, reflux and no doubt some genetic susceptibility

@ Dr. Mohammad H Derakhshan

Kindly see the link below.

https://gut.bmj.com/content/gutjnl/54/suppl_1/i1.full.pdf

Thanks!

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