Esophageal adenocarcinoma has the fastest growing incidence rate (300% increase over the past 4 decades) [1
], and the risk of patients with Barrett's Esophagus (BE) of developing adenocarcinoma is 30–120 times greater. BE is a change in the distal esophageal epithelium of any length that can be recognized as columnar-type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus [4
]. The currently accepted paradigm correlates the risk of progression to the grade of dysplasia as there is evidence that progression occurs in an orderly fashion from no dysplasia to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) followed by early esophageal adenocarcinoma [5
]. In addition esophageal adenocarcinoma has a poor survival rate (<5% at five years) due to a late diagnosis, to an early vascular and lymphatic infiltration and to low vascularization of neoplastic tissue, which leads to a low response to chemotherapy of the tumor [4
Since BE is considered the most important risk factor for the development of esophageal adenocarcinoma, assuming that the detection of mucosal dysplasia is critically important in patients with Barrett's oesophagus, because early diagnosis can prevent the progression to invasive carcinoma, international societies of gastrointestinal diseases suggest keeping patients in endoscopy surveillance program [5
However, surveillance endoscopy has several limitations because dysplastic changes occurring in BE are not easily identifiable by standard endoscopy.
In the last decades, many technologic advances have been done in the field of endoscopic imaging, through HR endoscopy to magnification endoscopy to virtual chromoendoscopy, in order to achieve a better visualisation of mucosal layer and to distinguish neoplastic versus nonneoplastic tissue. But even if good, new techniques are not strong enough to replace biopsies. Consequently, the current standard of endoscopic practice is to take multiple biopsies because there are no features on standard or HR endoscopy that distinguish Barrett's glandular metaplasia, dysplasia, or early-stage neoplasia. However the accuracy of standard white light endoscopy (WLE) and random biopsies is low and may fail to detect neoplastic lesions [7
]. Moreover biopsies obtained using this technique are prone to sampling error, and interobserver agreement is low even between advanced operators and even among expert pathologists [8
]. This results often in: (1) delay in reaching the final diagnosis and the decision of the correct and best treatment, (2) increased costs in pathology procedures, and (3) repeated procedures. In addition, sensitivity and specificity of histology are variable for difficulty to reach specimen adequacy. Moreover the presence of inflammation or ulcers could alter the mucosal architecture and give some false negative/positive results to pathology examination [10
]. A multiple biopsies protocol could also interfere with next therapeutic steps; endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) could be more difficult without adequate “lifting sign” due to scar tissue after repeated biopsies.
Nevertheless another important limitation of histology is that it is a postmortem analysis and it is not able to give us information about in vivo processes (blood flow).
Confocal laser endomicroscopy (CLE), a recent advance of endoluminal imaging, allows an in vivo visualization of mucosal layer with a detailed visualization of tissue and subcellular structures with magnification up to 1000 times. Since 2004 many papers, about the potential role of this new technique, have been published, and many studies have been introduced to validate this technique.
CLE has the potential to anticipate the final diagnosis (neoplastic versus nonneoplastic) and potentially to guide next therapeutic steps in clinical practice without the delay of a pathology response. Moreover it offers the possibility to study mucosal layer to a micron resolution giving us an “optical biopsy”. However, other technologies, such as narrow band imaging (NBI), autofluorescence imaging (AFI), and chromoendoscopy, are needed as “red-flag” techniques to initially detect and localize suspicious areas.
One of the potentially future applications of pCLE is about a role in in vivo study of physiologic and pathologic processes, like inflammation or angiogenesis in healthy or neoplastic tissue [15
Currently two devices are available and approved by European Medicines Agency (EMA) and Food and Drug Administration (FDA) to perform CLE: one system is inserted in tip of the scope (eCLE, Pentax Corporation, Tokyo, Japan) and one, a probe-based system, is a separate device from the endoscope but able to be introduced in the working channel of any standard endoscope (pCLE, Cellvizio, Mauna KeaTech, Paris, France).
In this system, the miniaturized confocal scanner has been integrated into the distal tip of a new endoscope. A blue laser light source delivers an excitation wavelength of 488
nm and light emissions detected at >505
nm. Successive points within the tissue are scanned in a raster pattern along X
-axis and Y
-axis to construct serial en face optical section of 475 × 475μ
m at user-controlled variable imaging depth. The optical slice thickness is 7μ
m with a lateral resolution of 0.7μ
m. Images on the screen approximate a 1000-fold magnification of the tissue in vivo [16
]. The advantage of this system is that the working channel of the scope is free, and it can be used for target biopsies or for combined enhancement techniques such as chromoendoscopy. The limit of this system is that the calibre of the scope is bigger than a standard 11.8
mm upper scope and is stiff. Moreover the lens of the scope is not combined with HR software and virtual chromoendoscopy or other system (ISCAN).
this system can be used through the working channel of any standard endoscope (colonoscope, gastroscope, cholangioscope, bronchoscope, and ureteroscop, etc). The advantage of this probe-based CLE is the versatility of the system and the possibility to combine it with other advanced “red flag” imaging modalities such as virtual chromoendoscopy or magnification. Scanning rates is 12 images/sec. The limits of this system pCLE are the slightly low power resolution compared to eCLE (1
mm versus 0.7
mm) and a small field of view (240–600
mm). So pCLE system is not well suited to surveying large areas of tissue such as long segments of BE and should ideally be combined with a red-flag technique for classification of tissue in a site already detected by enhanced endoscopy. However Mauna Kea has developed a postacquisition specifically-developed software (“mosaicing”) to paste images together and to obtain images similar to histology specimen.