Endoscopic Diagnosis and Treatment of Superficial Barrett Adenocarcinoma
Current status of endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma in Asia–Pacific region
Corresponding: Kenichi Goda, Department of Endoscopy, The Jikei University School of Medicine, 3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: firstname.lastname@example.org
The incidence of Barrett's adenocarcinoma has increased dramatically over the past few decades in most Western countries. While Barrett's esophagus is uncommon and adenocarcinoma is still rare in Asian populations, several Asian studies have indicated that the prevalence of esophageal adenocarcinoma is gradually increasing. Therefore, in order to determine the best way to treat superficial Barrett's adenocarcinoma, 12 expert endoscopists and a pathologist from the Asia–Pacific region conducted a session entitled ‘The current status of endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma’. After three keynote lectures, three Japanese panels presented cases of superficial Barrett's adenocarcinomas diagnosed by image-enhanced endoscopy (IEE). We then confirmed the results of a questionnaire on the diagnosis and treatment of superficial Barrett's adenocarcinomas. Finally, a panel introduced an Asia–Pacific international study on simplified narrow-band imaging (NBI) classification of Barrett's esophagus and neoplasias. After adiscussion, we proposed consensus statements on endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma as follows. Representative characteristics by conventional white light endoscopy are a reddish area or a lesion located on the anterior to right side wall. IEE may be useful for characterizing the tumor and diagnosing lateral tumor extension. Superficial Barrett's adenocarcinoma adjacent to the squamocolumnar junction is sometimes associated with subsquamous tumor extension. IEE may be useful to detect the subsquamous tumor extension especially when using NBI or an acetic acid-spraying method. Endoscopic mucosal resection or endoscopic submucosal dissection for mucosal carcinomas could provide excellent prognosis.
The incidence of Barrett's adenocarcinoma has increased dramatically over the past few decades in the West and accounts for more than 50% of all esophageal malignancies in the USA, Australia, and the Netherlands.[1, 2] Conversely, Barrett's esophagus (BE) is still uncommon and adenocarcinoma is rare in Asian populations. More than 95% of esophageal cancer in the Japanese population is squamous cell carcinoma. However, there have been many studies showing an increase in the number of patients diagnosed with gastroesophageal reflux disease (GERD) in Japan and other Asian countries over the last few decades.[3, 4] BE is thought to develop as a result of chronic GERD and predisposes to esophageal adenocarcinoma. A review article indicated that prevalence rates of esophageal adenocarcinoma have been gradually increasing in Singapore as well as in Japan.
Early detection of cancer followed by treatment offers the best prognosis. Therefore, Asia–Pacific endoscopists should verify the current status of endoscopic diagnosis and therapy of superficial Barrett's carcinoma (SBC) including high-grade dysplasia (which may be diagnosed as intraepithelial carcinoma by the vast majority of Japanese pathologists) or adenocarcinoma with invasion depth confined to the mucosal or submucosal layer. Also, we should determine the best way to detect and treat SBC by learning from endoscopists in West. We therefore conducted a session at Endoscopic Forum Japan (EFJ) 2012 at Otaru, Hokkaido, Japan, on 4 August. Twelve expert endoscopists and a pathologist from the Asia–Pacific region conducted a session entitled ‘The current status of endoscopic diagnosis and treatment of superficial Barrett's adenocarcinoma’.
First, three keynote lectures were given by three panels. Second, three Japanese panels presented cases of superficial Barrett's adenocarcinomas diagnosed by image-enhanced endoscopy (IEE). Third, we confirmed the results of a questionnaire survey on the diagnosis and treatment of superficial Barrett's adenocarcinomas that had been conducted with 10 Japanese panels prior to the EFJ meeting. We set inclusion criteria of the questionnaire survey as follows: SBC with invasion histologically confirmed by endoscopy or by surgically resected specimens from January 2006 to December 2010. Succeeding in collecting the data of 168 patients with 175 SBC, we analyzed them. Fourth, a panel introduced an Asia–Pacific international study on simplified narrow-band imaging (NBI) classification of BE and neoplasias. We invited expert endoscopists from the Asia–Pacific region including Australia and discussed and proposed consensus statements on the endoscopic diagnosis and treatment of SBC.
Diagnosis of BE
Two major problems remain in terms of the endoscopic and histological aspects of BE. These are the different anatomical criteria used in the definition of esophagogastric junction (EGJ), and the different histological criteria used to define BE.
Definition of EGJ
In Japan, the distal ends of palisade vessels are commonly the landmark of EGJ, whereas in the West, the proximal ends of gastric folds are taken as the landmark of EGJ according to The Prague C & M criteria. A representative study on The Prague C & M criteria indicated a significantly low kappa value of 0.21 in the diagnostic concordance of short segment <1 cm in length. Another study suggested a reason for the low kappa value in that gastric folds cannot be visualized when associated with severe atrophic gastritis, in particular the open type.
In the Japanese population, BE shows mostly the short segment and sometimes severe atrophic gastritis. Therefore, with regard to short-segment Barrett's esophagus (SSBE), the ends of palisade vessels are suggested to be more suited to the anatomical criteria than to the proximal ends of gastric folds.
Definition of BE
In most Western countries, histological evidence of goblet cells, so-called specialized intestinal metaplasia (SIM), is required to define BE because a metaplasia-dysplasia-adenocarcinoma sequence has been considered a mainstream of carcinogenesis. In contrast, the histological evidence of SIM is not required for the definition of BE in Japan and the UK. Recently, an increasing number of reports described that background non-goblet columnar epithelium might also be at risk for neoplastic progression as with SIM. In the session, all panels agreed that more importance may be placed on the endoscopic diagnosis of BE based on the anatomical criteria regardless of the histological evidence of goblet cells.
According to our questionnaire survey, more than three-quarters of patients were aged over 60 years. The vast majority of patients were male with esophagitis free or mild. Eighty-five percent of SBC was derived from SSBE. The rate of the presence of SIM was approximately 50%, but more than 80% of SIM lay adjacent to the SBC.
These questionnaire results suggested that SIM may not be mandatory to diagnose BE but will closely relate to the development of Barrett's adenocarcinoma through the hypothesis of the metaplasia-dysplasia-adenocarcinoma sequence.
Histology of Superficial Barrett's Adenocarcinoma
In the session, a panel of pathologists clarified four difficulties in making a diagnosis of superficial Barrett's adenocarcinoma. The first was the difference in the histological diagnosis of BE between Japan/UK and the other Western countries as aforementioned.
The second was the difference in the histological classification of Barrett's epithelial neoplasms between Japan and Western countries. Japanese pathologists diagnose gastrointestinal (GI) adenocarcinoma depending on the presence of invasion or architectural and cellular abnormalities, whereas Western pathologists diagnose based on the presence of invasion alone. Also, Japanese pathologists prefer to use the terminology of adenoma rather than dysplasia, unlike Western pathologists. In fact, our questionnaire survey revealed that Japanese pathologists diagnosed SBC accompanied by dysplasia at only 5%.
The third were the considerably low kappa values of <0.5 in diagnostic concordance that were seen in crypt dysplasia or low-grade dysplasia.
The fourth was the difficulty in the histological diagnosis of the lateral extension of Barrett's adenocarcinoma or dysplasia. One factor of this difficulty was associated with SBC showing mild architectural abnormality or SBC in dysplastic glands. Another factor was related to a lateral cancer extension beneath the squamous epithelium that we called ‘subsquamous tumor extension’ in the session. In the results of our questionnaire survey, 75 of 144 (52%) SBC that were adjacent to the squamocolumnar junction (SCJ) were associated with subsquamous tumor extension. The subsquamous tumor extension in 10 of 22 (45%) SBC were invisible by conventional white light endoscopy (WLE). ‘Subsquamous tumor extension’ could make it more difficult to diagnose lateral tumor extension for endoscopists as well as for pathologists.
Detection of superficial Barrett's adenocarcinoma
As with the questionnaire survey, in the session, SBC was defined as high-grade dysplasia or adenocarcinoma with invasion depth confined to the mucosal or submucosal layer. Random biopsy (e.g. Seattle protocol) is still the gold standard to identify dysplasia or adenocarcinoma in the West. Conversely, Japanese endoscopists usually carry out an endoscopically directed biopsy for a lesion suspected of dysplasia or adenocarcinoma. Also, IEE including staining dye-based (chromoendoscopy with dye solutions of indigocarmine, methylene blue, crystal violet etc.) or equipment-based techniques (NBI, autofluorescence imaging), and the acetic acid-spraying method have been applied to detect or characterize Barrett's neoplasia.[10-12] Recently, a prospective randomized controlled trial comparing standard endoscopy with random biopsies versus NBI targeted biopsies was published online. The trial showed NBI targeted biopsies could detect more areas with dysplasia. Moreover, regular appearing NBI surface patterns did not harbor high-grade/cancer, suggesting that biopsies could be avoided in these areas.
We searched a number of studies using various IEE techniques for SBC. We found the greatest number of studies using NBI and therefore NBI seems the most popular IEE technique to diagnose SBC. At the moment, NBI magnified endoscopy (NBIME) seems the most powerful tool to detect superficial carcinoma. The three major classifications of high-grade dysplasia or adenocarcinoma using NBIME were reported from Kansas, USA, Amsterdam, and Nottingham, UK. Those studies indicated significantly high diagnostic values, mostly over 90%. However, none of these NBI classifications has been in widespread use because these classifications are too complicated to use in clinical practice. Aiming at a widespread NBI classification, new attempts to simplify the NBIME classifications have recently been made. A panel introduced one of the attempts, which was called the Asia Pacific Barrett's Consortium. In this Asia–Pacific multicenter international study, pit and vascular patterns visualized by NBIME were divided into just three groups of surface patterns: regular pit and/or regular vasculature; irregular/absent pits and/or irregular vasculature; and not clear/unsure. The groups agreed that most NBI descriptors (pit and vasculature) could be classified into ‘regular’ for non-dysplastic and ‘irregular’ for dysplastic BE/early adenocarcinoma.
According to the simplified NBI classification, NBIME indicated significantly high diagnostic values (sensitivity/specificity/positive predictive value/negative predictive value: 89%/89%/56%/98%). We hope that the simplified NBI classification gains widespread use and leads to early diagnosis and treatment of Barrett's adenocarcinoma.
Our questionnaire results revealed that 157 of 175 (90%) SBC were visualized as a reddish lesion, 133 (76%) were located on the right or anterior side wall, and 91 (52%) showed an elevated type of macroscopic appearance. One hundred and sixty six (95%) were found by WLE alone without magnification and IEE. These results suggest that we should pay attention to a reddish area or a lesion located on the anterior to right side wall in screening or in surveillance endoscopy for BE. IEE may not be very helpful in detecting SBC lesions.
Preoperative Endoscopy of Superficial Barrett's Adenocarcinoma
Japanese panels usually use IEE for preoperative evaluation, in particular lateral extension of SBC. However, in the West, there have been few studies on the usefulness of IEE in preoperative diagnosis. Reasons why IEE is not common in the West were suggested as follows. In the West, Barrett's adenocarcinomas often arise from long-segment BE (LSBE). LSBE commonly has diffuse or patchy dysplastic lesions as well as synchronous or metachronous multiple cancers. This is because SBC have been thought to be treated along with non-neoplastic Barrett's epithelium in the West (e.g. by radiofrequency ablation [RFA]).
The bottom line seems to be that it is not necessary for Western endoscopists to diagnose lateral tumor extension in detail. In the West, there have been many studies on endoscopic detection or characterization, but no study on preoperative diagnosis of lateral tumor extension. All panels agreed to be rational and reasonable as there are many differences between Japan and the West in the clinical significance of IEE.
Endoscopic resection (ER) is the most common treatment for removal of SBC in Japan. A complete ER requires accurate preoperative diagnosis. Japanese panels always carry out IEE in order to diagnose lateral tumor extension accurately before ER. All panels agreed that IEE would be suitable to estimate lateral tumor extension but not tumor depth of SBC.
SBC adjacent to SCJ sometimes show lateral tumor extension beneath the squamous epithelium that we called ‘subsquamous tumor extension’. This is well known to expert endoscopists in the West as well as in Asia–Pacific. Subsquamous tumor extension is also known to be one of the factors that make it difficult to diagnose lateral tumor extension accurately by WLE. A histological correlation study reported that ultra-high-resolution optical coherence tomography succeeded in visualizing subsquamous Barrett's epithelium that was non-tumorous. However, little is known about whether IEE is useful in diagnosing subsquamous tumor extension. Therefore, we set subsquamous tumor extension as one of the important topics of the questionnaire and session.
Each of three Japanese panels demonstrated a case of SBC.[19, 20] They presented the usefulness of magnified IEE using NBI or the acetic acid-spraying method to diagnose lateral or subsquamous tumor extension of SBC.
Our questionnaire survey revealed that lateral tumor extension was diagnosed accurately by WLE in 97 (55%) SBC. IEE with magnification was useful in diagnosing lateral tumor extension accurately in 42 of 70 (60%) SBC that were invisible by WLE. Of 144 SBC adjacent to SCJ, 75 (52%) demonstrated subsquamous tumor extension. IEE with magnification plus NBI or the acetic acid-spraying method was useful in visualizing subsquamous tumor extension in 10 of 22 (45%) SBC with subsquamous tumor extension that were invisible by WLE. These questionnaire results suggest that magnified IEE may improve the diagnostic accuracy of lateral or subsquamous tumor extension by WLE.
Recently, RFA has become the most widely accepted therapy for SBC in Western countries. One of the concerns after any ablation technique (e.g. RFA, photodynamic therapy, argon plasma coagulation, and laser ablation) is residual subsquamous neoplasia or the development of subsquamous intestinal metaplasia, which could have the potential to progress to neoplasia. Consequently, we estimate that magnified IEE appears to be a potentially effective tool to detect subsquamous neoplasia after ablation techniques.
Endoscopic Therapy of Superficial Barrett's Adenocarcinoma
As mentioned earlier, Barrett's adenocarcinomas usually arise from SSBE in Japan, but often from LSBE in the West. LSBE is significantly different to SSBE in malignant potential. It has a carcinogenetic pattern with diffuse or patchy dysplastic lesions. Also, synchronous or metachronous multiple cancer occurrences are commonly seen in LSBE but not in SSBE.
In Japan, almost all SBC are removed by ER including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) if indicated. Adenocarcinomas from SSBE tend to be a single tumor without dysplastic lesions unlike those from LSBE. This may mean a low risk of recurrence in the remaining Barrett's epithelium after complete ER of SBC arising from SSBE. ER seems a reasonable technique to treat SBC in SSBE. Consequently, in the West, SBC have been thought to be treated along with non-neoplastic Barrett's epithelium. Thus, in recent times, RFA that can burn away not only SBC lesions but also background BE has become widely accepted by Western endoscopists as an ideal endoscopic treatment for SBC.
Our questionnaire survey showed that of the 175 SBC, 136 (78%) were removed by ER and 39 by esophagectomy (22%). ER was carried out for 111 mucosal carcinomas and 32 submucosal carcinomas. No patient died of SBC after ER for mucosal carcinomas during an observation period of longer than 2 years. Only one patient died of SBC after ER for submucosal carcinoma because of peritoneal dissemination associated with local recurrence. Also one patient died of SBC after esophagectomy as a result of developing systemic metastases after chemoradiotherapy for severe vascular invasion.
According to the questionnaire survey, ER could provide excellent prognosis for patients with mucosal carcinomas arising mainly from SSBE. Accurate preoperative diagnosis of lateral tumor extension using IEE might contribute to excellent prognosis after ER.
All panels in the Asia–Pacific region agreed to propose the following statements on the current status of endoscopic diagnosis and treatment of SBC.
- Endoscopic characteristics of SBC: Should pay attention to a reddish area or a lesion located on the anterior to right side wall.
- Diagnostic impact of IEE: Not very helpful to find SBC, but could be useful to characterize SBC or to diagnose lateral tumor extension.
- Endoscopic diagnosis of subsquamous tumor extension: A frequent, not rare, finding of SBC adjacent to SCJ, IEE may be useful particularly when using NBI or the acetic acid-spraying method.
- Endoscopic treatment: ER for mucosal carcinomas could provide excellent prognosis.
Conflict of Interests
Authors declare no conflict of interests for this article.