Gastrointestinal Endoscopy
Volume 71, Issue 2 , Pages 354-356, February 2010

Somewhere over the rainbow

Division of Gastroenterology and Hepatology, Professor of Medicine, Mayo Clinic College of Medicine, Jacksonville, Florida, USA

Article Outline

Abbreviations: CLE, confocal laser endomicroscopy, NBI, narrow-band imaging, OCT, optical coherence tomography, OFDI, optical frequency domain imaging

 

A major potential for optical frequency domain imaging, and particularly its mapping system, is to directly guide endoscopic ablation.

The endoscopic management of Barrett's esophagus associated neoplasia has traditionally been done by using endoscopic imaging with random biopsies, followed later by treatment. Endoscopic, as opposed to surgical, treatment is increasingly becoming the standard of care as evidenced by recent landmark studies on the effectiveness of radiofrequency ablation1 and photodynamic therapy.2 Proper treatment is predicated on accurate detection and precise localization of neoplasia. It has been well-known that routine endoscopic imaging with random biopsy has major limitations. More recently, methods such as high-definition, narrow-band imaging (NBI) have been shown to substantially increase the rate of detection and reduce the need for random biopsy.3 In this issue of Gastrointestinal Endoscopy, Suter et al4 demonstrate the feasibility of a new technique to detect pathology and direct biopsies in the esophagus.

These authors combined a new imaging method, optical frequency domain imaging (OFDI), with a method for marking the site of pathology by using a heat-generating laser, such that biopsy later can be directed to the site of pathology. The presumption of the study is that OFDI could be used to scan the entire esophagus for pathology, mark each abnormal site, and then perform endoscopic biopsy. To demonstrate feasibility, they performed the study in 5 pigs in whose esophagi they had previously placed artificial abnormalities. OFDI was used to scan the esophagus, create a highly precise, 3-dimensional reconstruction, and then use a second laser to make cautery “dots” at the site of the pathology. Sixty-eight artificial sites were made, and 97% of these were marked with a high degree of accuracy that allowed immediate endoscopic biopsy. The laser markings caused only superficial injury to the upper third of the mucosal layer, and follow-up for 2 days revealed no major complications.

From my perspective, this study achieves an important goal that many in the endoscopic imaging field have sought—namely, a highly precise method for marking and registration between an advanced imaging method and a biopsy site. The basic presumption that this technology could be used to guide biopsy is valid. There are, however, several key technical and conceptual limitations to applying OFDI-directed markings as they are outlined here.

First, a primer on OFDI. It is a technology similar to optical coherence tomography (OCT), which has been well-shown by this group and others to be a promising method for imaging Barrett's esophagus at micron-level resolution.5, 6 Both OCT and OFDI work much like US, except instead of using sound waves, they use light waves to create a 2-dimensional image. “Slices” or tomograms of tissue are separately imaged by using a principle called interferometry, in which light waves that are reflected from different layers of tissue (and thus different distances from the detector) are eliminated so that only images from a single slice are detected. OCT uses the “time of flight” of the light wave to precisely measure each slice (hence, OCT is sometimes called “time domain imaging”). When the detector is moved rapidly back and forth, a series of slices are stacked to create a 2-dimensional image. The resulting image is very precise, but the moving detector results in long image-acquisition times that make traditional OCT unsuitable for clinical purposes, although newer OCT systems are becoming considerably faster. OFDI overcomes this problem by using variations in light frequency (or wavelength) to image each slice. Through a complex mathematical analysis called Fourier tranform, each frequency and, thus, each slice can be resolved to create the 2-dimensional image. By using the frequency domain, instead of the time domain, OFDI can acquire images much faster than OCT. For example, the OFDI system in the current study can image a 6-cm length of Barrett's esophagus in 2 minutes.

Is marking important for dysplasia detection? All image-guided biopsy systems, from CT or magnetic resonance imaging to EUS, require precise registration between the site (such as a tumor) and the biopsy method (such as FNA). For nonendoscopic methods, such as OCT and OFDI, this has been problematic because the endoscopist cannot see where to take a biopsy sample. In the current study, Suter et al4 have made an important technological breakthrough by coupling an image laser with a high-energy laser capable of producing a superficial cautery mark at the precise location of an abnormality detected by OFDI. They clearly demonstrate that the sites seen on OFDI correspond pathologically to the abnormality in the esophagus.

The major limitation of OFDI is that simpler, highly accurate endoscopic systems already exist to guide biopsy, one of them being high-definition NBI. In recent studies, Wolfsen et al3 have shown that real-time endoscopic imaging with NBI can detect and directly guide biopsy to dysplasia in Barrett's esophagus. Although NBI does not replace biopsy nor provide staging information, it is simpler to use and already integrated into commercially available endoscopes. Confocal laser endomicroscopy (CLE) systems, both endoscope-based and probe-based, are also highly accurate for dysplasia classification and guiding biopsy, but they have very limited fields of view that require combination with broad-field imaging technologies such as NBI. OFDI does, however, offer the potential to provide both broad-field detection as well as staging information in Barrett's esophagus. This is a major shortcoming of current EUS systems that have poor accuracy for distinguishing high-grade intraepithelial neoplasia from T1 or T2 invasive cancer.

Could OFDI be used to screen for neoplasia in Barrett's esophagus? OCT has already been shown capable of distinguishing squamous esophagus from Barrett's esophagus with and without neoplasia in small, single-center studies.7, 8 We do not yet know whether OFDI will be able to make similar distinctions, although, in theory, it should. Early clinical case series by Suter et al9 have demonstrated proof of concept but not established efficacy. An appealing application of OFDI would be using this smaller, catheter-based system to perform population screening or surveillance on unsedated patients and to mark sites suitable for biopsy in patients with suspicious lesions. The fact that the authors could observe the cautery dots up to 2 days after imaging suggests that this would be feasible. Although the technique is promising, substantially more data are needed to establish the accuracy of OFDI in this setting, especially when disease prevalence is very low. Future studies should include patients with Barrett's esophagus with and without neoplasia, reviewed blinded to the histology, ideally in a multicenter environment.

Does this new platform lead to other possibilities? A major potential for OFDI, and particularly the mapping system shown here, is to directly guide ablation. Currently, in patients with focal neoplasia, we ablate the entire segment of Barrett's esophagus. This results in complications such as stricture formation and esophageal pain. A system such as the one shown here has tremendous potential. It could simultaneously map all regions of dysplasia or intestinal metaplasia, then an integrated ablation system could be used to destroy tissue. Clearly, the laser device used to make a cautery mark could also be adapted to cauterize a wider and deeper region of tissue. Furthermore, the coupling of laser ablation and laser detection is applicable to many other imaging methods such as OCT, spectroscopy, and confocal microscopy.

Another potential application of this platform is combining OFDI as a broad-field imaging method with more precise small-field methods to classify dysplasia and even replace biopsy. Highly accurate small-field systems already exist, including spectroscopic (autofluorescence, light scattering) and imaging methods (eg, CLE). All of these are based on laser light application, and thus have the potential for integration if one could get past the tongue-twisting (OFDI-AFI-LSS-CLE).

What technical hurdles exist to applying OFDI clinically? In the present study, images were performed in a pig esophagus with the animal under general anesthesia. The human esophagus, especially one altered by years of acid reflux, hiatal herniation, or prior biopsy and ablation, will present greater challenges. Although the authors argue that motion artifacts are not a major concern, I remain skeptical that a cough, hiccup, or incompletely sedated patient would not dislodge the centering balloon of the OFDI system during the 2-plus minutes it requires to image, interpret, and mark or ablate abnormal sites. Furthermore, the human esophagus, especially at the gastroesophageal junction in patients with Barrett's esophagus, is not cylindrical. Thus, a cylindrical balloon, as was used here to center the imaging fiber, is likely to move more easily and not precisely match the critical location. I agree with the authors' comments that noncylindrical balloons or low-compliance balloons, which conform to the shape of the esophagus, will be needed. As with all imaging methods, interobserver agreement through training, and ideally automated imaging recognition aids, will be important to wider application.

What does the future hold? After more than 2 decades of dedicated research in advanced optical systems, none of the systems have replaced endoscopy and biopsy. Any seasoned endoscopist has reasons to be skeptical of new technologies. What has changed dramatically over the past 3 to 5 years is bringing advanced methods of endoscopic imaging into routine clinical use. We already have seen commercially available NBI, other image-enhanced methods, and confocal imaging used in large, multicenter studies with highly effective results and now used in clinical practice. The pace of development has quickened such that other systems are coming on board rapidly.

In the screening and surveillance for the Barrett's esophagus setting, the ability to perform accurate, inexpensive examination of the esophagus on unsedated patients will be a critical breakthrough. OFDI technology, although not there yet, is in the ballpark.

For the treatment of early neoplasia in Barrett's esophagus, systems that integrate broad-field detection, small-field confirmation, and targeted ablation are no longer pie-in-the-sky dreams of Barrettologists. Although this puzzle remains incomplete, we can now see each of the necessary pieces. Indeed, as the song, “Somewhere Over the Rainbow” goes, “the dreams that you dare to dream really do come true”—but not without a lot of hard work, such as that done by Suter et al, presented here.

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Disclosure 

The author disclosed the following financial relationships relevant to this publication: Research and educational funding from Mauna Kea Technologies, Paris, France, Fujinon, Olympus, Center Valley, PA, Boston Scientific, Natick, MA, Cook Medical, Bloomington, IN and TAP/Takeda Pharmaceuticals, Deerfield, IL.

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References 

  1. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288
  2. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc. 2005;62:488–498
  3. Wolfsen HC, Crook JE, Krishna M, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett's esophagus. Gastroenterology. 2008;135:24–31
  4. Suter M, Jillella P, Vakoc B, et al. Image-guided biopsy in the esophagus through comprehensive optical frequency domain imaging and laser marking: a study in living swine. Gastrointest Endosc. 2010;71:346–353
  5. Isenberg G, Sivak JMV, Chak A, et al. Accuracy of endoscopic optical coherence tomography in the detection of dysplasia in Barrett's esophagus: a prospective, double-blinded study. Gastrointest Endosc. 2005;62:825–831
  6. Poneros JM. Diagnosis of Barrett's esophagus using optical coherence tomography. Gastrointest Endosc Clin N Am. 2004;14:573–588x
  7. Evans JA, Bouma BE, Bressner J, et al. Identifying intestinal metaplasia at the squamocolumnar junction by using optical coherence tomography. Gastrointest Endosc. 2007;65:50–56
  8. Evans JA, Poneros JM, Bouma BE, et al. Optical coherence tomography to identify intramucosal carcinoma and high-grade dysplasia in Barrett's esophagus. Clin Gastroenterol Hepatol. 2006;4:38–43
  9. Suter MJ, Vakoc BJ, Yachimski PS, et al. Comprehensive microscopy of the esophagus in human patients with optical frequency domain imaging. Gastrointest Endosc. 2008;68:745–753

PII: S0016-5107(09)02535-8

doi:10.1016/j.gie.2009.09.026

Gastrointestinal Endoscopy
Volume 71, Issue 2 , Pages 354-356, February 2010

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