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Clinical Journal of Gastroenterology (2018) 11:179–183 https://doi.org/10.1007/s12328-018-0863-3

CLINICAL REVIEW

Future of diagnosing neoplasia in Barrett’s esophagus: volumetric laser endomicroscopy

Muhammad Aziz1  · Rawish Fatima2

Received: 19 February 2018 / Accepted: 16 April 2018 / Published online: 21 April 2018 © Japanese Society of Gastroenterology 2018

AbstractEsophageal adenocarcinoma (EAC) is one of the deadliest carcinoma faced by gastroenterologists. Any insult to esophagus that causes replacement of normal squamous epithelium with columnar intestinal epithelium is labelled as the initiating event of the metaplasia–neoplasia sequence. Barrett’s esophagus is the precursor to EAC. Currently, endoscopically obtained biopsies are used to detect neoplastic changes in patients with Barrett’s esophagus (BE); however, it is not cost effective and hence a better screening modality is needed. Volumetric laser endomicroscopy (VLE) has been under study for the past few years and has shown promising results to overcome the shortcoming faced in the biopsy samplings. It is a second-generation optical coherence tomography (OCT) that provides high-resolution cross-sectional imaging of the esophageal mucosa using near-infrared light. The principle is similar to endosonography, but image formation in OCT depends on variations in the reflection of light from different tissue layers rather than ultrasonic waves.

Keywords Barrett’s esophagus · Esophageal adenocarcinoma · Optical coherence tomography · Volumetric laser endomicroscopy

Introduction

Esophageal cancer is ranked 6th among all cancer mortal-ity. It is one of the least studied and lethal cancer owing to its’ aggressive nature, lack of screening modality and poor survival rate [1]. Esophageal carcinoma has been associ-ated with smoking, drinking hot beverages, alcohol, being overweight, GERD, lack of fruits and vegetables in diet and Barrett’s esophagus [2]. There are two main types of esophageal carcinoma: Squamous cell carcinoma and adeno-carcinoma. Squamous cell carcinoma arises from squamous cells and can occur along the entire length of esophagus while adenocarcinoma develops from glandular cells and usually found in the lower third of esophagus. Replacement of esophageal squamous epithelium by glandular cells due to repetitive injury by any cause leads to the development

of adenocarcinoma. Barrett’s esophagus is the presumed precursor of esophageal adenocarcinoma. The incidence of EAC has risen rapidly over the past 25 years in the United States as well as in western European countries [2, 3]. The incidence of esophageal cancer reported for 2010–2014 was 4.2 per 100,000 people per year with mortality reported at 4.1 per 100,000 people per year [4]. This figure is alarming as it has not changed in the last decade due to paucity of data regarding better screening modalities as the current practice is not cost-effective.

Identifying people who have BE is a clinical challenge for clinicians with the current screening modalities and guidelines. Detecting neoplasia in patients with BE as part of surveillance is another daunting task that physicians come across due to limitations of random biopsy acquisition as part of Seattle protocol [5]. This calls for an advanced imag-ing technology that can examine neoplastic changes over vast areas of esophagus effectively in limited time. VLE is a relatively new technology that has shown potential to fulfill these needs. We performed an in-depth review of the litera-ture on articles published on VLE in association with BE and have summarized the important aspects.

* Muhammad Aziz maziz2@kumc.edu; marajani@hotmail.com

1 Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA

2 Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan

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Current practice to detect Barrett’s esophagus and surveillance

Endoscopically obtained biopsies and histological evalu-ation is the current gold standard for detecting BE and esophageal dysplasia. Guidelines generally recommend endoscopic surveillance in patients with Barrett’s esoph-agus at varying intervals corresponding to the degree of metaplasia shown in their biopsy. An interval of 3–5 years is suggested for patients without evidence of dysplasia, 6–12 months for patients with low grade dysplasia (LGD) and 3  months for patients with high-grade dysplasia (HGD) not receiving any invasive/ablative therapy [6]. The Seattle protocol is currently employed in which four quadrant biopsies are obtained at 1–2 cm interval through-out the length of esophagus [5]. Areas showing ulcera-tion, masses or any irregularities observed on endoscopy are also sampled. It is difficult to conclude if endoscopic surveillance is beneficial or not as observational studies that suggest that endoscopic surveillance reduces mortality from esophageal adenocarcinoma are susceptible to lead and length time biases making it difficult to agree upon a definitive conclusion [6]. Furthermore, biopsies using Seattle protocol is not cost-effective, time-consuming, and subject to sampling error with poor inter-observer agree-ment. Biomarkers and better imaging techniques are being investigated for this purpose.

Volumetric laser endomicroscopy

Volumetric laser endomicroscopy is a second generation optical coherence tomography (OCT) technology that utilizes low coherence interferometry to produce high-resolution images of biological tissue using back-scatter light intensity from a near infra-red light sources [7–10]. Its’ principle is similar to endosonography but image formation in optical coherence tomography depends on variations in the reflection of light from different tissue layers rather than ultrasonic waves also known as opti-cal frequency domain imaging (OFDI) signals [10]. This OCT- based technology called Fourier domain OCT or VLE is now commercially available; offering high imaging speed and improved sensitivity as compared to traditional OCT [8]. The NinePoints VLE system includes a balloon-centered probe and user console with monitor (Fig. 1). The probe is made up of a laser light source and optical sys-tem encircled by a transparent balloon with probe sizes ranging from 14 to 25 mm. After placement and infla-tion of the balloon in esophagus, the central component of the probe scans helically and simultaneously retracting

throughout the length of the balloon (6 cm). A data set is generated using interferometry and measurement of optical reflection delay from the laser light source. The scan takes 90 s to complete and produces circumferen-tial cross-sectional images of the tissue abutting the edge of the inflated balloon probe. Total, 1200 cross-sectional images are obtained from the mucosa to a depth of 3 mm. These images have a resolution of 7 µm making it compa-rable to low-power microscopy (Figs. 2, 3). VLE images are analyzed on a console that allows for simultaneous cross-sectional and longitudinal views. Additionally, a zoom view is available for both dimensions [7, 9, 10].

VLE in Barrett’s esophagus

The first clinical demonstration of endoscopic OCT for imaging of the human esophagus and stomach in vivo was performed by Sergeev et al. in 1997 [11]. A subsequent, more detailed assessment of OCT for esophageal diagnosis was performed in 2000 where OCT differentiated normal mucosa from BE, based on the lack of layered structure and

Fig. 1 Image of the NinePoint medical VLE console

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disorganized glandular morphology associated with BE [12]. Several studies in the literature have evaluated the role of VLE in diagnosing BE [11–20].

Safety and efficacy

A recent multicenter, prospective study, performed in patients with known or suspected BE demonstrated that the Nvision VLE Imaging System effectively achieved

completed scans (full 6-cm pullback that typically included the proximal stomach, gastroesophageal junction, and distal esophagus) in 87 cases out of 100 people with the remaining 13 cases were deemed a technical failure due to issues with probe and console. Furthermore, 77 out of these 87 patients underwent endoscopic biopsies with 54 (70%) mucosal abnormalities reported on the final pathology report. Minor mucosal tears were reported in 2 subjects that required no further intervention13. Another study assessed the safety of utilizing VLE for guidance to obtain biopsy in patients with the previous biopsy proven BE. VLE was not only shown to be safe (zero adverse events) but also displayed high accu-racy (93%) [17].

Diagnosing BE/neoplasia using VLE

VLE features that are predictive for Barrett’s esophagus were evaluated in a study. These included: (1) lack of layering; (2) higher surface than subsurface signal; (3) presence of irregular, dilated glands/ducts (Figs. 4, 5). The authors pro-posed novel criteria using these based on a point-scoring system. The criteria demonstrated sensitivity and specificity of 83 and 71%, respectively [16]. Another criterion called as Ocular coherent tomography—scoring index (OCT-SI) was proposed which included scoring based on gland architec-ture and surface maturation to establish a dysplasia index. This criterion exhibited a sensitivity and specificity of 83 and 75%, respectively at dysplasia index threshold of ≥ 2 [19]. Leggett et al. compared the OCT-SI with a novel scor-ing system called Volumetric laser endomicroscopy-Diag-nostic Algorithm (VLE-DA). The sensitivity, specificity and accuracy for OCT-SI was 70, 60 and 67% respectively at

Fig. 2 A cross-sectional image of an esophagus obtained from NinePoint Medical Clinical Study #15_01. Around 1 o’clock is an especially suspicious region, where the layering is partially effaced, dilated abnormal glandular structures are present in the mucosa, and the surface signal has intensified. The red lines represent aiming lines for laser cautery marks that were created in real time with the VLE Real-time Targeting laser marking system to target biopsies that were confirmed to be adenocarcinoma

Fig. 3 A co-registered white light endoscopy image showing the site of the abnormality seen in Image 2, and the superficial cautery marks created by the VLE laser marking system, to target biopsies at the site of the abnormality

Fig. 4 An example of NDBE when viewed with VLE. This is based on darker optical frequency domain imaging (OFDI) signal in deeper mucosa and few, regularly shaped acinar structures

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a dysplasia index threshold of ≥ 3, and for VLE-DA was 86, 88 and 87% respectively. Furthermore, the interobserver agreement for OCT-SI was fair (kappa 0.39) and substantial for VLE-DA (kappa 0.83). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < 0.01). The difference in dysplasia index threshold and lower statistical measures were explained due to the fact that Leggett et al. evaluated the images that were obtained on second-generation VLE imaging system as opposed to on the first-generation OCT when it was initially proposed [20].

Swager et  al. suggested a computer-based algorithm to evaluate VLE obtained images to identify BE. A sen-sitivity and specificity of 90 and 93% were reported that was reportedly higher than clinical VLE prediction score model (AUC 0.81) [14]. A case series on 6 biopsy-proven BE patients changed the management for all the patients after patient under VLE. The test upstaged the disease in five out of these six patients and they underwent radiof-requency ablation. The sixth patient had localization of a highly suspicious area that underwent endoscopic mucosal resection with biopsy revealing intramucosal cancer [18]. One study has also shown VLE to have potential of detecting sub-squamous esophageal structures (buried Barrett’s glands after radiofrequency ablation) [15].

VLE-guided laser marking was evaluated to be safe and effective in identifying suspicious areas concerning for malignancy in BE by Swagger et al. The technical success rate for this method was reported to be 97% and the sus-pected areas were correctly identified as evident on the biop-sies obtained [21]. VLE has also shown promise in terms of adaptability of technique and interpreting images obtained among novice users after receiving a brief tutorial [22].

Moreover, VLE has also shown strong interobserver agree-ment (kappa 0.66 and 0.79) for non-neoplastic and neoplas-tic BE as well as almost perfect agreement (kappa 0.95 and 0.86) for normal esophageal mucosa and gastric cardia [23].

Limitations

Although previous studies described several criteria includ-ing the VLE-DA and OCT-SI for detecting dysplasia in Barrett’s esophagus, these criteria were shown to poorly co-relate when trying to detect neoplastic changes. The VLE-DA and OCT-SI criteria were used by two VLE experts to successfully mark 18 sites for biopsy, however, pathology only demonstrated 33% of targeted areas with evidence of high-grade dysplasia and/or cancer [21]. Further, no sur-veillance protocol has been described for following patients with proven Barret’s esophagus with any form of dysplasia. Lastly, the widespread use of this new imaging technique has been limited given the added equipment cost and expertise to interpret the VLE images.

Conclusion

VLE is an emerging and promising technique that can be applied for detecting both non-neoplastic and neoplastic changes in patients with Barrett’s esophagus. It is safe and overcomes the limitations faced with endoscopy and biop-sies. More research including large center trials can pave the path for its widespread use in clinical settings. There is a need to formulate proper screening criteria to determine the diagnosis when interpreting VLE images.

Acknowledgements The authors would like to thank Mr. Pat Mac-Carthy of NinePoint Medical for supplying image 1–3 and Dr. Prateek Sharma of Kansas City VA medical center for supplying image 4–5 for this manuscript.

Compliance with ethical standards

Conflict of interest The Authors declare no conflict of interest whatso-ever in the preparation of this manuscript.

Human rights The manuscript is a review and does not involve any human subjects.

Informed consent Informed consent was not needed for preparation of this manuscript.

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Fig. 5 An example of HGD in a segment of Barrett’s viewed with VLE. In this image, the darker OFDI signal is more superficial, and there are many irregularly shaped acinar structures

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