Advanced or optical imaging in the esophagus allows for a detailed view of the esophagus at a level beyond white light endoscopy. The newest commercially available endoscopic advanced imaging tool is volumetric laser endomicroscopy (VLE) or second-generation optical coherence tomography. VLE is currently being used in management of Barrett’s esophagus, squamous cell dysplasia and cancer of the esophagus, and during peroral endoscopic myotomy. This review describes VLE and its current clinical applications to the esophagus.
The principle behind optical coherence tomography (OCT) is to measure the signal intensity of reflected light from a tissue sample. It is similar to endoscopic ultrasound but uses infrared light instead of an acoustic signal. OCT can produce high-resolution cross sectional imaging of the esophagus. The axial resolution is superior to high-resolution endoscopic ultrasound but at the expense of reduced depth of penetration compared to endoscopic ultrasound. The OCT probe is passed through a channel of an endoscope and once activated emits infared light. As light reflectivity from the esophageal tissue is measured, real time images of microscopic mucosal and submucosal changes are measured.
The mainstay of early OCT use in the esophagus was for Barrett’s esophagus. The older generation system consisted of a probe that was in gentle contact with the mucosa. A landmark study in 2001 showed that OCT could reliably distinguish between normal esophagus and intestinal metaplasia (IM).1 The study showed that normal squamous esophagus contained layered strictures while IM had loss of this layering or effacement. In 2006, OCT criteria were introduced to distinguish neoplastic IM of the esophagus (high- grade dysplasia and intramucosal cancer) from non- neoplastic IM.2 These criteria were derived from an in-vivo based study in which imaged areas with an OCT probe were then biopsied with a jumbo biopsy forceps. Histology was then compared to OCT images. Features indicative of neoplasia were 1) a high surface OCT signal to subsurface signal known as incomplete surface maturation and 2) glandular atypia. A scoring system, known as the OCT dysplasia scoring index (OCT-SI) or Evans criteria, was derived that indicated the likelihood of neoplasia in a Barrett’s segment imaged by OCT. When the dysplasia index is greater than or equal to two, a sensitivity and specificity of 83% and 75% was achieved, for diagnosing intramucosal cancer.
Second generation OCT, known as volumetric laser endomicroscopy (VLE), is somewhat different in that it is a balloon based system that contains the imaging probe. The probe is passed through the channel of the endoscope and the balloon is inflated to center the probe (Figure 1). The probe can then spin 360 degrees , emitting infrared light, and real time 360 degree cross sectional images of the esophagus are obtained. This technology is different from the probe-based system in that a whole 6 cm segment of the esophagus can be imaged in 90 seconds; a major improvement to the efficiency of this technology. In addition, the wide field imaging is a feature that other optical imaging platforms lack. This system is commercially available in the United States (Ninepoint Medical, Bedford, MA). The balloons currently come in 14 mm, 17 mm, and 20 mm. Specific details on the performing this procedure can be found in recent reviews of this topic but are beyond this review.3,4
Normal VLE Images
Normal squamous esophageal mucosa can be seen in Figure 2. It consists of layered architecture without glands in the epithelium. Pits and crypts, a hyperreflective or dark surface, and lack of layered architecture can be seen on VLE in normal gastric cardia (Figure 2).3-5?
VLE in Barrett’s Esophagus
In Barrett’s esophagus there is loss of layered architecture without any pits and crypts (to distinguish it from gastric mucosa). The features of neoplasia in VLE are generally the same features as first described in the probe based system.2 Recently two studies have further characterized neoplasia criteria for VLE using endoscopic mucosal resection specimen that were scanned using VLE ex-vivo.6,7 Leggett et al. devised a new scoring algorithm for neoplasia detection termed the VLE- DA.7 In this algorithm, the degree of effacement (loss of layering) is determined. If complete loss of layering is observed, then one observes the degree of surface to subsurface intensity. If the surface intensity is greater than the subsurface then dysplasia should be suspected. If partial effacement is observed then one determines the degree of atypical glands, if present. If greater than 5 atypical glands is present than one should suspect dysplasia. Based on this algorithm, the sensitivity and specificity for dysplasia detection was 86 and 88% respectively. Figure 3 shows examples of nondyspalstic and dysplastic Barrett’s esophagus. Swager et al. also looked at EMR specimens that underwent VLE scanning and determined three independent VLE features that predict dysplasia: effacement, higher surface to subsurface signal, and the presence of atypical dilated ducts/glands.6 They developed a VLE prediction score assigning certain points for each feature. Both criteria are similar, but in clinical practice the VLE-DA is somewhat more practical to use. In addition, effacement is commonly seen, and in our clinical experience not associated with dysplasia. Currently, physicians in practice use these criteria to help guide them when looking for images that possible contain dysplasia. The interobserver variability for VLE image interpretation is favorable.8 Given both the Leggett and Swager criteria are based on ex-vivo EMR specimens, in-vivo research is needed to validate these criteria.
In mid 2016, laser marking became commercially available, allowing physicians to mark abnormalities seen on VLE on the esophageal mucosa. The commercially available model was an upgrade from that used in human pilots.9 The physician has the option of placing one or two superficial laser marks at sites of VLE abnormalities. This allowed the ability to target lesions specifically rather than estimating where the abnormality was based on the registration line on the balloon and the VLE scan and relation to the abnormality from the GE junction. To date there are case reports and series showing the benefit of VLE in clinical practice.5,10?-14 Figure 4 shows an example of a case where VLE with laser marking helped diagnose Barrett’s with high- grade dysplasia. Our group presented findings at the American College of Gastroenterology 2017 meeting showing an incremental yield of dysplasia detection in patients with Barrett’s esophagus who underwent surveillance endoscopy with VLE with laser marking compared to patients that underwent VLE without laser marking or patients that had traditional Seattle protocol surveillance biopsies.15 Currently there is an ongoing multi- center prospective dysplasia detection pilot to confirm in-vivo criteria of dysplasia.
An anticipated upgrade to the VLE system in the near future will be computer automated detection of VLE abnormalities. Although the learning curve for VLE image interpretation seems favorable,16 many VLE image frames are presented to the user at one time and thus it is possible to miss a suspicious area. A recent computer algorithm pilot based on VLE EMR specimens showed good performance to detect Barrett’s associated neoplasia.17 Addition of this feature will make VLE more user friendly to endoscopists.
VLE in Squamous Cell Dysplasia and Cancer
The vast majority of esophageal cancers occur in the non-western world with ninety percent of these being esophageal squamous cell carcinoma (ESCC).18 The precursor to ESCC is squamous intraepithelial neoplasia (SIN).19 Endoscopic therapy is accepted for ESCC and SIN if the lesions are limited to the epithelium or lamina propria.19,20 Lesions limited to the mucscularis mucosa or superficial submucosa are considered a gray zone for endoscopic treatment19,20 These standards of therapy are based on the risk of lymph node metastasis (LNM).21,22
Determining which patients have ESCC limited to the lamina propria can be challenging. In a recent retrospective study, specimens from patients that underwent ESD for flat ESCC, were examined.20 The study showed that one third of patients that met clinical and endoscopic criteria for RFA had histologic criteria that were considered contraindications for RFA. The study concluded that determining which patients should receive RFA therapy is challenging. The challenge stems from inaccurate pre-therapy staging of ESCC.23 High-frequency endoscopic ultrasound (HF- EUS) and EUS are limited in imaging superficial ESCC.23 However, studies have shown that optical coherence tomography (OCT) can produce high- resolution images of staging ESCC. A prospective study compared OCT to HF-EUS in 123 patients with superficial ESCC and found that OCT had a higher accuracy (95% vs 81%; p<0.05).23 The probe based first generation OCT, used in that study, is not commercially available.
There is limited experience on the use of VLE for staging superficial squamous cell cancer of the esophagus. In our experience we have found that VLE can be helpful for squamous dysplasia/SIN or superficial cancers involving up to the lamina propria. This staging is based on OCT signal penetration into a layer with preservation of the layers below it. In VLE staging of SIN, a surface hyperreflective (darker) signal from the neoplasm is visualized only involving the epithelium with preservation of the layers below it (Figure 5).24 However with disease involving deeper layers, a surface hyperreflectivity is seen with effacement (loss of the traditional layering) below the darkened surface. The extent or depth of disease involvement is determined by which layers are preserved below it. If there is involvement of the muscularis mucosa or deeper, a surface hyperreflectivity is seen, with complete effacement of all layers below it. An example of a SIN lesion is seen in Figure 5. Studies are needed to confirm our findings. If studies confirm our findings, than it is conceivable that VLE can guide appropriate endoscopic therapy for SIN (RFA or resection) and superficial squamous cell esophageal cancer limited to the lamina propria (RFA or endoscopic resection). Disease determined to involve the muscularis mucosa based on EUS/ VLE could be candidates for endoscopic resection by endoscopic mucosal resection or endoscopic submucosal resection technique.
VLE Use in Peroral Endoscopic Myotomy
Peroral endoscopic myotomy (POEM) has emerged as a first line treatment for achalasia.25 A POEM consists of creation of an esophageal submucosal tunnel, and subsequent myotomy of the distal esophageal circular and lower esophageal sphincter muscles. It is unclear if the tunnel and subsequent myotomy should be in the anterior versus posterior approach.26 Desai and colleagues examined if pre-procedure VLE imaging could determine the optimal approach.26 In this multi- center international registry, they compared outcomes of patients that underwent a VLE tailored POEM versus a traditional POEM. In a VLE tailored exam, if the pre-procedure VLE scan showed a thickened anterior muscle, then the patient underwent an anterior approach. On the other hand if the patient had a thickened posterior muscle (Figure 6) then they underwent a posterior approach. If they had a thickened circumferential muscle, then the approach was dictated by the presence of vasculature. If anterior vessels were noted, then a posterior approach was used. If posterior vessels were noted, then an anterior approach was used.
A total of 84 patients were included in the study by Desai et al. Fifty-one patients underwent pre-POEM VLE. Twenty-four and twenty-seven patients underwent an anterior and posterior approach respectively. Technical success was achieved in 96% of patients. Statistically significant less bleeding was observed in the VLE group versus the traditional group (8% vs 43%, p<0.0001). As a result procedural times was less in the VLE group compared to the traditional group, despite the time taken to perform the VLE (86 min vs 122 min, p=0.0001). This study is limited in that there are no validated scaled scoring systems in place to measure the muscle thickness, however the concept is promising. Further research is needed to show if VLE pre-POEM can indeed reduce peri-procedural bleeding and reduce procedure time.
VLE is a tool that can be used in the esophagus to help guide diagnosis of neoplasia and aid or guide the correct endoscopic therapy. The majority of procedures to date have been in Barrett’s esophagus. Not surprising, most of the literature supporting its use is in Barrett’s as well. Although further studies are needed showing the incremental yield of VLE in diagnosing dysplasia, the preliminary data being presented is encouraging. VLE?s potential for guiding staging and therapy in squamous cell esophageal cancer is also promising and may guide which therapy to perform. Finally, the use of pre- procedural POEM may improve outcomes during the procedure. Further studies using computerized measurements of muscle thickness of the VLE scans are needed to validate this approach.