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Research review

Emerging enhanced imaging technologies of the esophagus: spectroscopy, confocal laser endomicroscopy, and optical coherence tomography Lourdes Y. Robles, MD,a Satish Singh, MD,b and Piero Marco Fisichella, MD, MBAc,* a

Department of Surgery, University of California Irvine Division of Gastroenterology, Boston VA Healthcare System, Boston University, Boston, Massachusetts c Department of Surgery, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts b

article info

abstract

Article history:

Background: Despite advances in diagnoses and therapy, esophageal adenocarcinoma re-

Received 17 November 2014

mains a highly lethal neoplasm. Hence, a great interest has been placed in detecting early

Received in revised form

lesions and in the detection of Barrett esophagus (BE). Advanced imaging technologies of

4 February 2015

the esophagus have then been developed with the aim of improving biopsy sensitivity and

Accepted 18 February 2015

detection of preplastic and neoplastic cells. The purpose of this article was to review

Available online 21 February 2015

emerging imaging technologies for esophageal pathology, spectroscopy, confocal laser endomicroscopy (CLE), and optical coherence tomography (OCT).

Keywords:

Methods: We conducted a PubMed search using the search string “esophagus or esophageal

Spectroscopy

or oesophageal or oesophagus” and “Barrett or esophageal neoplasm” and “spectroscopy or

Inelastic (Raman)

optical spectroscopy” and “confocal laser endomicroscopy” and “confocal microscopy” and

scattering spectroscopy

“optical coherence tomography.” The first and senior author separately reviewed all arti-

Optical coherence tomography

cles. Our search identified: 19 in vivo studies with spectroscopy that accounted for 1021

Barrett esophagus

patients and 4 ex vivo studies; 14 clinical CLE in vivo studies that accounted for 941 patients

Confocal laser endomicroscopy

and 1 ex vivo study with 13 patients; and 17 clinical OCT in vivo studies that accounted for

Confocal microscopy

773 patients and 2 ex vivo studies. Results: Human studies using spectroscopy had a very high sensitivity and specificity for the detection of BE. CLE showed a high interobserver agreement in diagnosing esophageal pathology and an accuracy of predicting neoplasia. We also found several clinical studies that reported excellent diagnostic sensitivity and specificity for the detection of BE using OCT. Conclusions: Advanced imaging technology for the detection of esophageal lesions is a promising field that aims to improve the detection of early esophageal lesions. Although advancing imaging techniques improve diagnostic sensitivities and specificities, their integration into diagnostic protocols has yet to be perfected. ª 2015 Elsevier Inc. All rights reserved.

* Corresponding author. Department of Surgery, Boston VA Healthcare System, Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132. Tel.: þ1 857 203 5549; fax: 857 203 3545. E-mail address: [email protected] (P.M. Fisichella). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.02.045

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1.

Introduction

The sensitivity of white light endoscopy alone for the detection of Barrett esophagus (BE) is limited [1,2]. In a Veterans Affairs cooperative study, 192 patients with GERD were examined with standard endoscopy with biopsy specimens performed by different endoscopists and found a change in diagnosis in 18% of patients with BE. Inconsistencies in the ability to detect intestinal epithelium were common in this study [1]. Current practice guidelines originally published in 1998 by the American College of Gastroenterology mandate the biopsy of tissue to determine cellular details. Biopsy protocols for BE have been recommended; however, they are not evidence based and include random biopsies every 2 cm with large capacity forceps performed every 3e5 y [3]. The drawback of random biopsies is that they are associated with sampling of tissue of less than 1% in an area of potential interest [4]. Moreover, as illustrated by Falk et al. [5], there are considerable variations in biopsy intervals and techniques used by endoscopists in the United States. In addition, the random biopsy method lends itself to erroneous outcomes and detection errors. The ability to identify microstructural pathology in vivo is insurmountably important in the detection of cellular abnormalities and any technology that could provide target-directed biopsies (rather than random) would increase the detection of abnormal cells and alter current diagnostic, therapeutic, and surveillance protocols. Enhanced imaging techniques of the esophagus have been developed over the years with the aim of improving biopsy sensitivity and detection of preplastic and neoplastic cells. This article aims to provide a review on three emerging imaging technologies for the detection of esophageal pathology as follows: spectroscopy, confocal laser endomicroscopy (CLE), and optical coherence tomography (OCT). They propose to transform the diagnostic, therapeutic, and surveillance approach to patients with BE by providing targeted, real-time, microstructural details of tissue in vivo. We specifically aimed at describing the techniques, their history and evolution, their current applications, and propose a framework for future research.

2.

Materials and methods

Scoping searches in PubMed were conducted using the search string “esophagus or esophageal or oesophageal or oesophagus” and “Barrett or esophageal neoplasm” and “spectroscopy or optical spectroscopy” and “confocal microscopy or confocal endomicroscopy or confocal laser endomicroscopy” and “optical coherence tomography.” The search was performed to scope suitable articles within the past 10 y. The first and senior author separately reviewed all articles. In addition, we did not enforce any limits because of the novelty of techniques, so that articles with a wide range of cases reported have been intentionally included; however, articles that did not have an English language translation were excluded. Reviews were likewise excluded. Our search focused on the application of spectroscopy, CLE, and OCT identified; 19 in vivo studies with spectroscopy that accounted for 1021 patients

503

and 4 ex vivo studies; 14 clinical CLE in vivo studies that accounted for 941 patients and 1 ex vivo study with 13 patients; and 17 clinical OCT in vivo studies that accounted for 773 patients and 2 ex vivo studies. The details of the studies and their findings are summarized in Tables 1e3. Because of the novelty of the technology, we have not established inclusion or exclusion criteria, with the goal to retrieve as many articles as possible.

3.

Emerging imaging technologies

3.1.

Spectroscopy

Optical spectroscopy is a technique that uses microstructural information contained in light-tissue interactions to enhance abnormal tissue recognition during standard endoscopy. This technology could transition standard BE surveillance from random biopsies to a real-time “optical biopsy” [62]. The main types of spectroscopy include fluorescence, elastic scattering, and inelastic (Raman) scattering [63]. Fluorescence spectroscopy is based on the principle that when a beam of light with a particular wavelength hits a fluorophore, it excites electrons. Then, when the fluorophore relaxes and goes back to ground state, it emits light of lower energy and longer wavelength, producing a fluorescent fingerprint [64]. Different tissues such as normal tissue, intestinal metaplasia, and dysplasia produce different fluorescence signals [17]. Inelastic (Raman) scattering spectroscopy measures signals produced when light undergoes shifts in wavelength with energy transfer in tissues. This technology exploits the shifts in light wavelengths that are caused by vibrations of common molecular bonds found in tissues. The Raman spectrum is a direct measurement of the molecular composition of the underlying tissue. Pathologic tissues have different vibrations and thus different shifts in light wavelengths compared with those of normal tissue [63]. Elastic scattering spectroscopy (ESS) measures scattering events, which happen when wavelengthdependent light reflects from tissue before reflecting back toward the source [63]. ESS exploits the fact that light scatters differently in normal and in neoplastic tissues [65]. ESS is not an imaging modality, although it provides point spectroscopic measurements and samples a tissue volume of 2, sensitivity and specificity were 83% and 75% for IMC/HGD Fine features (cribriform, viliform glandular architecture) was seen more clearly on UHR-OCT Algorithm developed for diagnosing intestinal metaplasia HR-OCT enables improved resolution and visualization of subtle features OCM provided cellular details of specimens, whereas OCT provided complementary information over a larger field of view OCT was able to identify squamous BE epithelium in vivo

[43] [44]

The accuracy for detecting epithelium and lamina propria was significantly higher than EUS Residual glands were seen during RFA sessions correlating with treatment response Buried glands were found in 72% patient pre-RFA and 63% post-RFA

HGD ¼ high grade dysplasia; GI ¼ Gastrointestinal; IMC ¼ Intra Mucosal Cancer; OCM ¼ Optical Coherence Microscopy; EUS ¼ Endoscopic Ultrasound.

[45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57]

[58] [59] [60] [61]

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Author

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Fig. 1 e The integrated ESS biopsy system for in situ endoscopic tissue diagnosis measures scattering events, which happen when wavelength-dependent light (Xenon) reflects from tissue before reflecting back toward the source. A standard ESS catheter probe samples predominantly the mucosal layer, with each measurement taking approximately 30 ms. Scatter characteristics generate spectral signs that correlate with histologic features such as size, shape, nuclear-cytoplasmic ratio, and cell cluster patterns. (Color version of the figure is available online.)

one by Rodriguez-Diaz et al. [20]. The integrated system improved the sensitivity and specificity of diagnosing esophageal pathology to 88% and 94%, respectively, for dysplastic BE from gastric columnar epithelium. Several authors have used spectroscopy for in vivo esophageal imaging (Table 1) and report enhanced sensitivity and specificity over standard endoscopy and histology for identifying dysplasia and cancer. In a more recent clinical study, Boerwinkel et al. [27] theorized that fluoroscopic spectroscopy would have resulted in 50% less biopsy specimens taken in patients with BE compared with those in random biopsies taken with a standard endoscope. Taking technology one step further, spectroscopic OCT that performs in a functional endoscope channel has also been developed [66]. It is yet to be determined if this is superior to either imaging technology in vivo.

3.2.

Confocal laser endomicroscopy

CLE is based on the principle of illuminating tissue with the use of a low-power laser and then detecting the florescent light reflected from the tissue. The laser is focused at a specific depth and only the light reflected back from the plane is refocused through a pinhole confocal aperture. Thus, scattered light from below and above the plane of interest is not detected and special resolution is enhanced. The examined area is scanned in the horizontal and vertical planes, and an image is reconstructed [67]. CLE relies on tissue florescence, and intravenous or topical-applied contrast agents are always required. Fluorescein-based imaging provides in vivo magnification of the mucosa of 1000-fold [68] (Fig. 2). The Food Drug Administration has approved two systems as follows: a

confocal laser endomicroscope and a flexible confocal miniprobe. Only the confocal miniprobe is currently commercially available. This unit has both the laser scanning unit and light source outside the patient’s body. The probes are extremely flexible and can be passed through the working channel of a standard endoscope. A 488-nm laser beam is transmitted through several optical fibers within the probe. The same fibers act to reflect the fluorescent light to a distal object. Depending on the probe type, the depth of imaging ranges from 0e100 m and can be adjusted. With the plethora of advanced imaging technologies currently available, the American Society for Gastrointestinal Endoscopy set out to establish performance guidelines that would be required for a real-time “optical biopsy” to replace the standard random biopsy protocol [69]. These thresholds include a per-patient sensitivity of 90% or greater, a negative predictive value of 98% or greater, and a specificity of 80% for the detection of high-grade dysplasia or neoplasia. A meta-analysis looking at CLE, performed by Wu et al. [70], investigated the data from eight studies from 2000e2012 that involved 709 patients. The results of pooled data from four studies demonstrated a per-patient sensitivity for the detection of neoplasia of 89% with a specificity of 75%. The reported pooled per-lesion sensitivity of seven studies, which reported diagnostic accuracy of CLE for the detection of neoplasia, was 70% with a specificity of 90%. At meta-analysis, the pooled sensitivity for detection of neoplasia was calculated at 70% with a specificity of 91%. Sampling error may have contributed to the low per-location sensitivity because it was possible the CLE images did not correlate with the site from which the biopsy samples were taken. Conversely, Canto et al. [42] were the first to demonstrate that an advanced imaging technology

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Fig. 2 e CLE in which normal squamous esophagus, nondysplastic BE, dysplastic BE, and neoplastic BE are compared side by side. Panel (A) shows normal squamous esophagus with “flat scale-like” cells typical of the normal squamous epithelium; panel (B) shows nondysplastic BE with dark goblet cells and mucinous columnar cells characteristic of columnar epithelium (arrow); panel (C) shows an increased number of glands with irregular forms, darker cells compared to surrounding structures, and a thick, dark epithelial-stripe in villous architecture (arrow); and panel (D) shows neoplastic BE with a highly disorganized epithelium, loss of cell structure and polarity, and vessels leaking into the cellular interstitium (arrow). (Color version of the figure is available online.)

surpassed the thresholds established by the American Society for Gastrointestinal Endoscopy. In the prospective, randomized control trial, one hundred ninety-two patients undergoing BE surveillance were randomized to undergo high definition white light endoscopy (HDWLE) with random biopsies or HDWLE and CLE with targeted biopsies. The study found that the addition of CLE led to a statistically lower number of mucosal biopsies with a threefold diagnostic yield for cancer detection compared with the random biopsy method (35% versus 7%). Moreover, CLE eliminated the need for biopsies in 65% of patients. The sensitivity of detecting neoplasia was increased to 96% from 40% with a slight reduction in sensitivity (92% versus 98%), and the treatment plan was changed because of a corrected change in the dysplasia grade with the use of CLE in 36% of patients. This study established a crucial outcome, in that it demonstrated the targeted biopsy method was superior to standard random biopsies. Conflicting randomized trials make the interpretation of results of CLE trials challenging. For instance, a prospective randomized trial by Wallace et al. [39] demonstrated no significant benefit for the addition of CLE to HDWLE. One hundred nineteen patients were randomized to undergo HDWLE or HDWLE with CLE for the determination of residual BE 2e4 mo after ablation. The study failed to provide evidence that the combination of HDWLE and CLE was superior to CLE

alone. The reasons for the failure were unclear to the authors as the accuracy for assessment of residual BE was significantly lower in this study compared with that in other studies, including their own [35]. Moreover, a cautionary argument must be established when discussing CLE as virtually all the data developed on CLE are from academic centers with highly specialized endoscopists with a greater prevalence of identifying BE compared with general practice.

3.3.

Optical coherence tomography

Van Dam and Fujimoto [71] described OCT as the most noteworthy advance in imaging of the gastrointestinal tract since endoscopic ultrasound (US). OCT is a revolutionary technology that is analogous to US B-mode imaging but uses light as the signal instead of sound [63]. This technology is based on interferometry, in which light from a source is divided into two beams as follows: one that is directed toward the tissue and the other that is directed toward a moveable reference mirror whose location can be measured. An interference signal is obtained when backscattered light from tissue and light reflected from the mirror reach the detector at the same time. These signals are then processed into algorithms that can be displayed in real-time images. The main advantage of OCT is that OCT images have a 10-fold greater resolution compared to high-resolution US imaging.

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Fig. 3 e UHR-OCT of normal squamous layered mucosa and its correspondent hematoxylin and eosin biopsy stain. (Color version of the figure is available online.)

Interferometry has been described since the 1800s; however, it has not been applied clinically until the last decade. The clinical birthplace of OCT was in ophthalmology [72]. In vitro studies of the human retina and optical disc established the first topographic human tissue image with precise microstructural detail. These studies provided the framework for using OCT for different histotypes. OCT had only begun to be used clinically in 1991 but was quickly adapted to examine BE in vivo in 1997 [43]. Several in vivo studies have confirmed the utility of OCT (Table 3) and have reflected the rapid evolution of the technology. Standard OCT uses superluminescent diode light sources and is limited by attenuation of scattering from tissue. Also, optical depths approach 2e3 mm and axial resolution of 10e15 mm, which are comparable to conventional biopsy. However, although depths are limited, resolution is 10-fold greater than that of US [46]. Standard OCT has an impressive sensitivity and specificity, but it is fraught with false positives and proves difficult when distinguishing cardiac or junctional

type mucosa [50]. Furthermore, several investigators use different OCT systems, lending itself to variability in reporting [73]. Further refinements in OCT were established to mediate some of these issues. With the incorporation of broadband optical light, ultra high resolution (UHR)-OCT is able to achieve an axial resolution of 1e2 mm [74]. Using a new broadband Cr4þ Forsterite laser source, Herz et al. were able to establish the first UHR-OCT for in vivo feasibility assessment in a rabbit. The UHR-OCT images resulted in a 5-mM axial resolution in air corresponding to 3.7 mm in tissue, which is indicative of two to three times finer resolution than standard OCT. The higher axial resolution corresponded to enhanced visualized tissue morphology in situ. Therefore, UHR-OCT resulted in an overall improvement in quality image. Chen et al. [54] found that UHR-OCT images corresponded to histologic features greater than 83% of the time in multiple tissues. (Figs. 3e5) Taking it one step further, three dimensional (3D)-OCT became possible because of the dramatic increases in imaging speeds [75]. 3DOCT has a 5-mm axial resolution, a 14-mm lateral resolution,

Fig. 4 e UHR-OCT suspicious for BE with goblet cells characteristic of columnar epithelium (arrows).

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Fig. 5 e UHR-OCT suspicious for high grade dysplasia with large and irregular glands (arrows).

and a tissue depth of 1.5 mm. Using a standard prototype, Adler et al. [76] were able to capture 300 mm3 of tissue volume in 20 s. 3D-OCT offers fields of view that are orders of magnitude larger and increased imaging depths. Zhou et al. [77] used 3D-OCT in BE and found that OCT features matched, associated, stained histology specimens. Progress in development of computer-aided imaging software may further provide a more user-friendly application to OCT. It has yet to be determined if real-time optical biopsies on a patient under sedation would occur in a time appropriate fashion and would equal the time a pathologist spends surveying a mounted slide. Computer programs that improve tissue evaluation are essential, as they would assist in diagnosing optical biopsies without the necessity of further training in histopathology [78]. BE is defined by the presence of specialized intestinal metaplasia and is recognized as a precursor of esophageal adenocarcinoma [79]. Retrospective studies have discovered a survival benefit if esophageal cancers are detected by surveillance [80,81]. As discussed previously, the random biopsy method lends itself to error, and OCT technology may improve the detection of esophageal cancers at their very earliest stages. Pitris et al. [47] determined the feasibility of OCT on ex vivo human surgical specimens and found high microstructural resolutions. The squamous epithelium of the normal esophagus was clearly contrasted with the nonuniform mucosal layers of BE. Cobb later used UHR OCT for ex vivo studies on 14 patients who underwent esophagectomy. The authors clearly identified BE on the surgical specimens although there were difficulties in distinguishing some Barrett glands from blood vessels because of the lack of blood flow [58]. Nevertheless, these studies paved the way for in vivo assessments and prospective studies.

In the first prospective studydalso the largest powered study, with 121 patients, dthree criteria were established by the authors to diagnose BE. These included lack of normal esophageal morphology, inhomogeneous tissue contrast, and presence of submucosal glands. The presence of at least two of these criteria was found to be 97% sensitive and 92% specific when compared with histology [49]. In a separate elegant study, UHR-OCT was used to guide biopsy specimens of 113 patients undergoing endoscopy. A pathologist blinded to the use of OCT reviewed the tissue and graded the 196 biopsy specimens as gastric cardia, squamous mucosa, pancreatic metaplasia, or intestinal metaplasia. An algorithm was then established based on 40 biopsy-correlated OCT images. This algorithm was then used by two separate blinded investigators to review 123 OCT images and found a sensitivity of 81% for both investigators [55]. However, accuracy was diminished when the algorithm was applied to the training set for identifying gastric cardia and intestinal metaplasia. A potential explanation for this phenomenon given by the authors was perhaps inadequate tissue representation in the training set, a registration error, or even motion artifact. Furthermore, the authors stated errors of only a few millimeters likely contributed to misdiagnosis by OCT. It stands to reason that proper standardization of this technique will need to explore improved training and establish better criteria to improve diagnostic accuracy. Not all studies have had immediate success with OCT. Isenberg et al. prospectively examined 314 biopsy-associated OCT images by four blinded endoscopists and found a high sensitivity and specificity for detecting dysplasia; however, high grade dysplasia had a 50% sensitivity and 72% specificity [52]. One of the major drawbacks with OCT is the subjective interpretation of the data, which imparts interobserver variability. Image artifacts and quality of the data continue to be

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issues with the technology. For instance, in the study of Isenberg et al., 12% of the images were eliminated due to technical reasons [52]. However, years of improvements in the technology have enabled improved visualization. In a welldesigned study, 3D-OCT was performed on 27 patients before and after radiofrequency ablation (RFA) for BE. The authors found an astonishing 63% of patients with residual intestinal metaplasia of the esophagus after complete RFA eradication [61]. Similarly, Tsai et al. [60] found the presence of visible glands immediately after RFA, which correlated to the presence of residual, BE with 90.6% accuracy. The studies by Tsai and Zhou highlight another potential application to OCT, as a guide to real-time RFA retreatment decisions.

4.

5.

511

Conclusions

In conclusion, this review highlighted the current clinical application of advanced imaging techniques for the identification of BE. More studies are needed to determine how OCT, CLE, and spectroscopy are going to be integrated into diagnostic protocols. Likewise, future-randomized trials between optical biopsies and standard histology need to occur to prove the hypothesis that real-time tissue characteristics aid in improving biopsy methods, enhances detection of pathologic states, anddabove alldreduces morbidity and mortality for patients undergoing screening or treatment for dysplasia and cancer.

Future research Acknowledgment

Several points of contention are suggested by Peery and Shaheen [82] in regard to the clinical application of OCT, which are relevant to the discussion of CLE, and spectroscopy as well. 1. Improved sensitivity and specificity in diagnosing dysplasia would need to be accomplished in a large number of participants to make the technology clinically applicable. There is a wide range of sensitivities and specificities among authors of studies using OCT and a high interobserver variability. 2. OCT should quickly and accurately survey the distal esophagus. Unfortunately, image quality, data processing time, and the ability to perform concomitant biopsies have not been clearly outlined in current OCT studies. 3. To truly consider this technology as an optical biopsy that guides tissue biopsies and determines treatment options in real time, the imaging would need to be obtained in a timely manner. Two studies note that imaging of the distal esophagus can occur in only 4 min [75,83]; however, interpretation of images occurred after endoscopy and was described as “time consuming” [75,83]. 4. Given the potential for large volumes of data that may be created from OCT, a method to select clinically relevant images would provide a more efficient system. As mentioned previously, computer-aided programs may be the solution to this problem. 5. Finally, cost effectiveness must always be a consideration in this rapidly changing health care system. The economics of this technology are unclear, and moreover, the impact is also unclear. Will this technology aid in treating BE before advancement to cancer? This question has yet to be answered. Boerwinkel et al. [84] had similar concerns regarding advanced imaging techniques. He indicated that advanced imaging techniques have limited value for detection of BE lesions that would require a resection. He states that expert BE endoscopists will always detect lesions on HDWLE that will require resection. Although advanced imaging technology may detect microscopic flat lesions that cannot be seen on standard endoscopy, these are of clinically limited value because these lesions will effectively be eradicated by ablation.

Authors’ contributions: P.M.F. and S.S. contributed to the study conception and design and the critical revision. L.Y.R. did the acquisition of data. P.M.F., S.S., and L.Y.R. did the analysis and interpretation of data. P.M.F. and L.Y.R. did the drafting of the article.

Disclosure L.Y.R. and P.M.F. have no conflicts of interest to declare. S.S. has received educational support from Mauna Kea Technologies.

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