Confocal Endomicroscopy in Barrett’s Esophagus: A New Tool or Toy?
William R. Brugge, MD, FAGA
Director, Gastrointestinal Endoscopy, Massachusetts General Hospital, GI Unit, Boston
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The detection, diagnosis and staging of early neoplastic lesions and other digestive diseases are some of the principal aims of gastrointestinal endoscopy. High-definition white-light endoscopy (HD-WLE) is currently the standard of care, and under proper conditions, endoscopy can detect early gastrointestinal malignancy. When mucosal abnormalities are detected, they are usually biopsied or resected and submitted for histologic analysis. This current practice of histological analysis is associated with delays in diagnosis and management. Until recently, this time-honored and resource-intensive protocol had not been challenged. This tradition has now been brought into question with the recent development and novel application of confocal microscopy coupled with gastrointestinal endoscopy, termed confocal laser endomicroscopy (CLE).
Indications and considerations for use
The current indications for the use of CLE include clinical scenarios that require histologic sampling of the target mucosa. CLE imaging of the gastrointestinal mucosa enables endoscopists to obtain real-time histologic images as well as enhance the guidance of physical mucosal biopsies. The general indications for the use of CLE include the identification of premalignant mucosa and the rapid diagnosis of benign mucosal disease.
There are two manufacturers for CLE: 1) Pentax Medical (Tokyo, Japan) in joint partnership with Optiscan Pty. Ltd. (Notting Hill, Melbourne, Australia) and 2) Cellvizio, Mauna Kea Technologies (Paris, France). The Pentax confocal system obtains images via a confocal microscope integrated within the distal tip of an endoscope (eCLE), thus limiting its use to the alimentary tract. The Cellvizio system acquires confocal images via a fiber optic mini-probe that can be passed through the accessory channel of an endoscope (pCLE). This system, given its flexible design, allows use in the alimentary tract in addition to the biliary and pancreatic ducts, and targeted organs via endoscopic accessories (i.e., catheters and biopsy needles).
A contrast agent is critical for endoscopic confocal imaging, and fluorescein is most commonly used. Once administered intravenously, there is a dramatic highlighting of vascular structures and the mucosa, lasting about 20 minutes. Although fluorescein sodium can be topically applied, it performs poorly for imaging deeper mucosal layers. Transient hypotension, nausea or injection-site erythema occurs in less than 1 percent of patients.
Clinical indications for CLE
The strongest indication for the use of CLE is in the detection of Barrett’s esophagus and associated dysplasia and neoplasia. CLE can readily detect the mucosal changes of Barrett’s epithelium. In contrast to the normal squamous mucosa (which appears as a bland array of elliptical cells), intestinal metaplasia appears as a villous-like epithelium (see figure below). One potential role of CLE might be to screen for Barrett’s esophagus in high-risk individuals (e.g., older males with chronic GERD) who will undergo endoscopy with biopsy. The accuracy of CLE in differentiating between esophagitis, Barrett’s and gastric epithelium is more than 90 percent. In a large study, Barrett’s esophagus and associated neoplasia could be predicted with a sensitivity of 98.1 percent and 92.9 percent, and a specificity of 94.1 percent and 98.4 percent, respectively (overall accuracy: 96.8 percent and 97.4 percent). The potential advantage of using CLE would be to decrease the dependence on biopsies in the diagnosis of Barrett’s eosphagus. Unfortunately, these cost savings might be offset by the cost of equipment and training.
CLE can also be used for the detection of early malignancy arising in patients with known Barrett’s esophagus. In this clinical scenario, patients with well-established Barrett’s esophagus who undergo surveillance endoscopy and CLE would be candidates for CLE. The role of CLE could be in the detection of dysplasia and the guidance of biopsies to suspicious sites. In a recent study, CLE-guided targeted biopsies of Barrett’s doubled the diagnostic yield of endoscopy for the detection of Barrett’s neoplasia from 17.2 percent to 33.7 percent. In addition to improving the yield of endoscopic biopsies, CLE could also reduce the need for routine surveillance biopsies in Barrett’s mucosa without evidence of dysplasia. Currently, there is a large prospective international multicenter study underway to assess the performance characteristics of eCLE in patients with Barrett’s and associated neoplasia (ClinicalTrials.gov Identifier: NCT01124214). Figure: Examples of confocal endomicroscopy of esophageal squamous epithelium (1a), Barrett’s epithelium (1b) and intramucosal carcinoma (1c).
Probe-based CLE studies in Barrett’s esophagus
The use of CLE with a probe has great appeal because of its ease of use and ability to target small suspicious lesions arising in Barrett’s. The initial studies comparing the sensitivity of pCLE against histology in patients with Barrett’s esophagus were disappointing. However, pCLE criteria for the diagnosis of Barrett’s-associated neoplasia have been better developed and published. A two-fold increased sensitivity has been demonstrated (from 34 to 68 percent) in the detection of early neoplasia using CLE.
Recently, an international, multicenter, randomized, controlled trial compared pCLE with HD-WLE in 101 consecutive patients with Barrett’s esophagus. The authors investigated the comparative sensitivities of HD-WLE, narrow band imaging and pCLE. The combination of pCLE with HD-WLE significantly improved the diagnostic ability to detect Barrett’s-associated neoplasia over HD-WLE alone. The sensitivity and specificity for detecting neoplasia with HD-WLE were 34.2 percent and 92.7 percent compared to 68.3 percent and 87.8 percent with pCLE. Furthermore, pCLE detected many more neoplastic lesions than HD-WLE alone.
In summary, confocal endoscopic microscopy holds great promise to aid the endoscopist in the diagnosis of Barrett’s esophagus and the early neoplasia associated with Barrett’s esophagus. With the recent approval of a CPT code for confocal endomicroscopy, we will see increasing use of this new endoscopic imaging technique.
Dr. Brugge received grants from Asuragen and RedPath.