Molecular imaging is a rapidly growing new discipline in gastrointestinal endoscopy. It uses the molecular signature of cells for minimally-invasive, targeted imaging of gastrointestinal pathologies. Molecular imaging comprises wide field techniques for the detection of lesions and microscopic techniques for in vivo characterization. Exogenous fluorescent agents serve as molecular beacons and include labeled peptides and antibodies, and probes with tumor-specific activation. Most applications have aimed at improving the detection of gastrointestinal neoplasia with either prototype fluorescence endoscopy or confocal endomicroscopy, and first studies have translated encouraging results from rodent and tissue models to endoscopy in humans. Even with the limitations of the currently used approaches, molecular imaging has the potential to greatly impact on future endoscopy in gastroenterology.
Molecular imaging; endoscopy; confocal endomicroscopy; autofluorescence imaging; cancer; EGFR
Upper gastrointestinal tract cancers are one of the most important leading causes of cancer death worldwide. Diagnosis at late stages always brings about poor outcome of these malignancies. The early detection of precancerous or early cancerous lesions of gastrointestinal tract is therefore of utmost importance to improve the overall outcome and maintain a good quality of life of patients. The desire of endoscopists to visualize the invisibles under conventional white-light endoscopy has accelerated the advancements in endoscopy technologies. Nowadays, image-enhanced endoscopy which utilizes optical- or dye-based contrasting techniques has been widely applied in endoscopic screening program of gastrointestinal tract malignancies. These contrasting endoscopic technologies not only improve the visualization of early foci missed by conventional endoscopy, but also gain the insight of histopathology and tumor invasiveness, that is so-called optical biopsy. Here, we will review the application of advanced endoscopy technique in screening program of upper gastrointestinal tract cancers.
It is well known that angiogenesis is critical in the transition from premalignant to malignant lesions. Consequently, early detection and diagnosis based on morphological changes to the microvessels are crucial. In the last few years, new imaging techniques which utilize the properties of light-tissue interaction have been developed to increase early diagnosis of gastrointestinal (GI) tract neoplasia. We analyzed several “red-flag” endoscopic techniques used to enhance visualization of the vascular pattern of preneoplastic and neoplastic lesions (e.g. trimodal imaging including autofluorescence imaging, magnifying endoscopy and narrow band imaging). These new endoscopic techniques provide better visualization of mucosal microsurface structure and microvascular architecture and may enhance the diagnosis and characterization of mucosal lesions in the GI tract. In the near future, it is expected that trimodal imaging endoscopy will be practiced as a standard endoscopy technique as it is quick, safe and accurate for making a precise diagnosis of gastrointestinal pathology, with an emphasis on the diagnosis of early GI tract cancers. Further large-scale randomized controlled trials comparing these modalities in different patient subpopulations are warranted before their endorsement in the routine practice of GI endoscopy.
Angiogenesis; Autofluorescence imaging; Multiband imaging; Narrow band imaging; Zoom endoscopy
Early detection of malignancies within the gastrointestinal tract is essential to improve the prognosis and outcome of affected patients. However, conventional white light endoscopy has a miss rate of up to 25% for gastrointestinal pathology, specifically in the context of small and flat lesions within the colon. Chromoendoscopy and other advanced imaging techniques aim at facilitating the visualization and detection of neoplastic lesions and have been applied throughout the gastrointestinal tract. Chromoendoscopy, particularly in combination with magnifying endoscopy has significantly improved means to detect neoplastic lesions in the gastrointestinal mucosa, particularly in ulcerative colitis and Crohn’s colitis. In addition, chromoendoscopy is beneficial in the upper gastrointestinal tract, especially when evaluating Barrett’s oesophagus (BO) for the presence of dysplasia. Furthermore, it also improves characterization, differentiation and diagnosis of endoscopically detected suspicious lesions, and helps to delineate the extent of neoplastic lesions that may be amenable to endoscopic resection. This review discusses the dyes, indications and advanced endoscopic imaging methods used in various chromoendoscopic techniques, and presents a critical overview of the existing evidence supporting their use in current practice with a particular emphasis on the role in inflammatory bowel disease and BO.
Endoscopic diagnosis currently relies on the ability of the operator to visualize abnormal patterns in the image created by light reflected from the mucosal surface of the gastrointestinal tract. Advances in fiber optics, light sources, detectors, and molecular biology have led to the development of several novel methods for tissue evaluation in situ. The term “optical biopsy” refers to methods that use the properties of light to enable the operator to make an instant diagnosis at endoscopy, previously possible only by using histological or cytological analysis. Promising imaging techniques include fluorescence endoscopy, optical coherence tomography, confocal microendoscopy, and molecular imaging. Point detection schemes under development include light scattering and Raman spectroscopy. Such advanced diagnostic methods go beyond standard endoscopic techniques by offering improved image resolution, contrast, and tissue penetration and providing biochemical and molecular information about mucosal disease. This review describes the basic biophysics of light-tissue interactions, assesses the strengths and weaknesses of each method, and examines clinical and preclinical evidence for each approach.
The emergence of endoscopy for the diagnosis of gastrointestinal diseases and the treatment of gastrointestinal diseases has brought great changes. The mere observation of anatomy with the imaging mode using modern endoscopy has played a significant role in this regard. However, increasing numbers of endoscopies have exposed additional deficiencies and defects such as anatomically similar diseases. Endoscopy can be used to examine lesions that are difficult to identify and diagnose. Early disease detection requires that substantive changes in biological function should be observed, but in the absence of marked morphological changes, endoscopic detection and diagnosis are difficult. Disease detection requires not only anatomic but also functional imaging to achieve a comprehensive interpretation and understanding. Therefore, we must ask if endoscopic examination can be integrated with both anatomic imaging and functional imaging. In recent years, as molecular biology and medical imaging technology have further developed, more functional imaging methods have emerged. This paper is a review of the literature related to endoscopic optical imaging methods in the hopes of initiating integration of functional imaging and anatomical imaging to yield a new and more effective type of endoscopy.
Endoscopy; Functional imaging; Multi-modal imaging; Optical coherence tomography; Fluorescence molecular imaging; Photoacoustic tomography; Cerenkov luminescence tomography
Cancer surveillance is an increasing part of everyday practice in gastrointestinal endoscopy due to the identification of high risk groups from genetic and biomarker testing, genealogic and epidemiologic studies, and the increasing number of cancer survivors. An efficient surveillance program requires a cost-effective means for image-guided cancer detection and biopsy. A laser-based tethered-capsule endoscope with enhanced spectral imaging is introduced for unsedated surveillance of the lower esophagus. An ultrathin version of this same endoscope technology provides a 1.2-mm guidewire with imaging capability and cannula-style tools are proposed for image-guided biopsy. Advanced 3D cell visualization techniques are described for increasing the sensitivity of early cancer diagnosis from hematoxylin-stained cells sampled from the pancreatic and biliary ducts.
endoscope; biopsy; image-guided intervention; 3D cytology; cancer surveillance
The field of endoscopy has revolutionized the diagnosis and treatment of gastrointestinal (GI) diseases in recent years. Besides the ‘traditional’ endoscopic procedures (esophagogastroduodenoscopy, colonoscopy, flexible sigmoidoscopy, and endoscopic retrograde cholangiopancreatography), advances in imaging technology (endoscopic ultrasonography, wireless capsule endoscopy, and double balloon enteroscopy) have allowed GI specialists to detect and manage disorders throughout the digestive system. This article reviews various endoscopic procedures and provides up-to-date endoscopic indications based on the recommendations of American Society for Gastrointestinal Endoscopy and American Cancer Society for primary care providers in order to achieve high-quality and cost-effective care.
endoscopy; endoscopic indications; endoscopic procedures; imaging; primary care; gastrointestinal disorders; appropriate use
Molecular imaging is a rapidly growing new discipline in gastrointestinal endoscopy that involves the development of novel imaging probes and instruments to visualize the molecular expression pattern of mucosa in the digestive tract. Several platforms for imaging agents, including antibody and peptide, are being developed to target over expressed biomolecules in cancer. In addition, novel imaging instruments, including fluorescence endoscopy and confocal microscopy, are being developed to provide wide area surveillance and microscopic examination. These methods are being applied to detect the presence of flat and depressed colonic neoplasms and to identify the tumor margins.
molecular imaging; colonic neoplasms; dysplasia; flat and depressed; targets
Real-time visualization of the molecular signature of cells can be achieved with advanced targeted imaging techniques using molecular probes and fluorescence endoscopy. This molecular optical imaging in gastrointestinal endoscopy is promising for improving the detection of neoplastic lesions, their characterization for patient stratification, and the assessment of their response to molecular targeted therapy and radiotherapy. In inflammatory bowel disease, this method can be used to detect dysplasia in the presence of background inflammation and to visualize inflammatory molecular targets for assessing disease severity and prognosis. Several preclinical and clinical trials have applied this method in endoscopy; however, this field has just started to evolve. Hence, many problems have yet to be solved to enable the clinical application of this novel method.
Molecular imaging; Endoscopy; Fluorescence probe; Intestinal diseases
The future of endoscopy will be dictated by rapid technological advances in the development of light sources, optical fibers, and miniature scanners that will allow for images to be collected in multiple spectral regimes, with greater tissue penetration, and in three dimensions. These engineering breakthroughs will be integrated with novel molecular probes that are highly specific for unique proteins to target diseased tissues. Applications include early cancer detection by imaging molecular changes that occur before gross morphological abnormalities, personalized medicine by visualizing molecular targets specific to individual patients, and image guided therapy by localizing tumor margins and monitoring for recurrence.
Endoscopic imaging is in part responsible for the recent drop in deaths from gastrointestinal cancers and also for detecting pre-cancerous and non-cancerous conditions and allowing them to be treated effectively, although techniques are far from perfect. Endoscopic imaging has evolved considerably from fiber optic systems 50 years ago to high resolution and high definition systems used at present. Moreover, image enhancement using filters and processors has led to the technique of ‘electronic chromoendoscopy’ to visualize mucosal blood vessels and surface pit patterns clearly. Magnification by optical zoom or confocal laser microscopy has enabled real time diagnosis and ‘virtual histology’. These techniques have contributed to the early detection, assessment and treatment of various gastrointestinal pathologies. The focus of future research is directed towards molecular targeted imaging.
This special September issue of Clinical Endoscopy will discuss various aspects of diagnostic and therapeutic advancement of gastrointestinal (GI) endoscopy, explaining what is new in digestive endoscopy and why international network should be organized. We proposed an integrated model of international conference based on the putative occurrence of Digestive Endoscopy Networks. In International Digestive Endoscopy Network (IDEN) 2012, role of endoscopy in gastroesophageal reflux disease and Barrett's esophagus, endoscopy beyond submucosa, endoscopic treatment for stricture and leakage in upper GI, how to estimate the invasion depth of early GI cancers, colonoscopy in inflammatory bowel disease (IBD), a look into the bowel beyond colon in IBD, management of complications in therapeutic colonoscopy, revival of endoscopic papllirary balloon dilation, evaluation and tissue acquisition for indeterminate biliopancreatic stricture, updates in the evaluation of pancreatic cystic lesions, issues for tailored endoscopic submucosal dissection (ESD), endoluminal stents, management of upper GI bleeding, endoscopic management of frustrating situations, small bowel exploration, colorectal ESD, valuable tips for frustrating situations in colonoscopy, choosing the right stents for endoscopic stenting of biliary strictures, advanced techniques for pancreaticobiliary visualization, endoscopic ultrasound-guided biliopancreatic drainage, and how we can overcome the obstacles were deeply touched. We hope that IDEN 2012, as the very prestigious endoscopy networks, served as an opportunity to gain some clues for further understanding of endoscopic technologies and to enhance up-and-coming knowledge and their clinical implications from selected 25 peer reviewed articles and 112 invited lectures.
IDEN; Network; Digestive endoscopy
Endoscopy has undergone explosive technological growth in over recent years, and with the emergence of targeted imaging, its truly transformative power and impact in medicine lies just over the horizon. Today, our ability to see inside the digestive tract with medical endoscopy is headed toward exciting crossroads. The existing paradigm of making diagnostic decisions based on observing structural changes and identifying anatomical landmarks may soon be replaced by visualizing functional properties and imaging molecular expression. In this novel approach, the presence of intracellular and cell surface targets unique to disease are identified and used to predict the likelihood of mucosal transformation and response to therapy. This strategy can result in the development of new methods for early cancer detection, personalized therapy, and chemoprevention. This targeted approach will require further development of molecular probes and endoscopic instruments, and will need support from the FDA for streamlined regulatory oversight. Overall, this molecular imaging modality promises to significantly broaden the capabilities of the gastroenterologist by providing a new approach to visualize the mucosa of the digestive tract in a manner that has never been seen before.
endoscopy; molecular imaging; targets; early detection
Currently, in gastrointestinal endoscopy there is increasing interest in high resolution endoscopic technologies that can complement high-definition white light endoscopy by providing real-time subcellular imaging of the epithelial surface. These ‘optical biopsy’ technologies offer the potential to improve diagnostic accuracy and yield, while facilitating real-time decision-making. Although many endoscopic techniques have preliminarily shown high accuracy rates, these technologies are still evolving. This review will provide an overview of the most promising high-resolution imaging technologies, including high resolution microendoscopy, optical coherence tomography, endocytoscopy and confocal laser endoscopy. This review will also discuss the application and current limitations of these technologies for the early detection of neoplasia in Barrett’s esophagus, ulcerative colitis and colorectal cancer.
Microendoscopy; Confocal laser endoscopy; Endocytoscopy; High-resolution; Optical coherence tomography; Barrett’s esophagus; Ulcerative colitis; Colon cancer
Barrett's esophagus (BE) is an acquired condition characterized by replacement of stratified squamous epithelium by a cancer predisposing metaplastic columnar epithelium. Endoscopy with systemic biopsy protocols plays a vital role in diagnosis. Technological advancements in dysplasia detection improves outcomes in surveillance and treatment of patients with BE and dysplasia. These advances in endoscopic technology radically changed the treatment for dysplastic BE and early cancer from being surgical to organ-sparing endoscopic therapy. A multimodal treatment approach combining endoscopic resection of visible and/or raised lesions with ablation techniques for flat BE mucosa, followed by long-term surveillance improves the outcomes of BE. Safe and effective endoscopic treatment can be either tissue acquiring as in endoscopic mucosal resection and endoscopic submucosal dissection or tissue ablative as with photodynamic therapy, radiofrequency ablation and cryotherapy. Debatable issues such as durability of response, recognition and management of sub-squamous BE and optimal management strategy in patients with low-grade dysplasia and non-dysplastic BE need to be studied further. Development of safer wide field resection techniques, which would effectively remove all BE and obviate the need for long-term surveillance, is another research goal. Shared decision making between the patient and physician is important while considering treatment for dysplasia in BE.
Barrett’s esophagus; endoscopic mucosal resection; endoscopic submucosal dissection
During the last decade, researchers have made great progress in the development of new image processing technologies for gastrointestinal endoscopy. However, diagnosis using conventional endoscopy with white light optical imaging is essentially limited, and ultimately, we still rely on the histopathological diagnosis from biopsy specimens. Molecular imaging represents the most novel imaging methods in medicine, and the future of endoscopic diagnosis is likely to be impacted by a combination of biomarkers and technology. Endoscopic molecular imaging can be defined as the visualization of molecular characteristics with endoscopy. These innovations will allow us not only to locate a tumor or dysplastic lesion but also to visualize its molecular characteristics and the activity of specific molecules and biological processes that affect tumor behavior and/or its response to therapy. In the near future, these promising technologies will play a central role in endoluminal oncology.
Gastrointestinal neoplasms; Technology; Molecular imaging
Obscure gastrointestinal bleeding (OGIB) is defined as bleeding from the gastrointestinal tract that persists or recurs after a negative initial evaluation using bidirectional endoscopy and radiologic imaging with small-bowel radiograph. The main challenges related to evaluation of OGIB include the high miss rate for lesions on initial evaluation with standard endoscopy and the limited capacity of older diagnostic modalities to effectively examine the small bowel. The introduction of capsule endoscopy, balloon-assisted enteroscopy, spiral enteroscopy, and computed tomography (CT) enterography have served to overcome the limitations of older diagnostic tests. Capsule endoscopy is currently recommended as the third test of choice in the evaluation of patients with OGIB, after a negative bidirectional endoscopy. Balloon-assisted enteroscopy is useful for both the diagnosis and endoscopic management of OGIB. CT enterography is superior to small-bowel radiograph for luminal and extraluminal small-bowel examination. These advances in small-bowel diagnostics and the capacity to successfully perform endoscopic therapeutics have largely replaced surgical procedures and resulted in a trend toward noninvasive evaluation and endoscopic management of OGIB.
Obscure gastrointestinal bleeding; video capsule endoscopy; balloon-assisted enteroscopy; double-balloon enteroscopy; single-balloon enteroscopy; spiral enteroscopy; computed tomography enterography
Detection of premalignant lesions in the upper gastrointestinal tract may facilitate endoscopic treatment and improve survival. Despite technological advances in white light endoscopy, its ability to detect premalignant lesions remains limited. Early detection could be improved by using advanced endoscopic imaging techniques, such as magnification endoscopy, narrow band imaging, i-scanning, flexible spectral imaging color enhancement, autofluorescence imaging, and confocal laser endomicroscopy (CLE), as these techniques may increase the rate of detection of mucosal abnormalities and allow optical diagnosis. The present review focuses on advanced endoscopic imaging techniques based on the use of CLE for diagnosing premalignant lesions in Barrett esophagus and stomach.
Barrett esophagus; Stomach neoplasms; Endoscopy; Confocal laser endomicroscopy; Molecular imaging
Imaging strategies that detect early-stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2-cre;p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions.
mouse model; neoplasm; extracellular matrix; POSTN
Recent advances in optical molecular imaging allow identification of morphologic and biochemical changes in tissues associated with gastrointestinal (GI) premalignant lesions earlier and in real-time. This focused review series introduces high-resolution imaging modalities that are being evaluated preclinically and clinically for the detection of early GI cancers, especially Barrett esophagus and esophageal adenocarcinoma. Although narrow band imaging, autofluorescence imaging, and chromoendoscopy are currently applied for this purpose in the clinic, further adoptions of probe-based confocal laser endomicroscopy, high-resolution microendoscopy, optical coherence tomography, and metabolomic imaging, as well as imaging mass spectrometry, will lead to detection at the earliest and will guide predictions of the clinical course in the near future in a manner that is beyond current advancements in optical imaging. In this review article, the readers will be introduced to sufficient information regarding this matter with which to enjoy this new era of high technology and to confront science in the field of molecular medical imaging.
Gastrointestinal premalignant lesions; Barrett esophagus; Imaging mass spectrometry; Biological markers
Cholangioscopy not only enables the direct visualization of the biliary tree, but also allows for forceps biopsy to diagnosis early cholangiocarcinoma. Recently, some reports have suggested the clinical usefulness of direct peroral cholangioscopy (POC) using an ultra-slim endoscope with a standard endoscopic unit by a single operator. Enhanced endoscopy, such as narrow band imaging (NBI), can be helpful for detecting early neoplasia in the gastrointestinal tract and is easily applicable during direct POC. A 63-year-old woman with acute cholangitis had persistent bile duct dilation on the left hepatic duct after common bile duct stone removal and clinical improvement. We performed direct POC with NBI using an ultra-slim upper endoscope to examine the strictured segment. NBI examination showed an irregular surface and polypoid structure with tumor vessels. Target biopsy under direct endoscopic visualization was performed, and adenocarcinoma was documented. The patient underwent an extended left hepatectomy, and the resected specimen showed early bile duct cancer confined to the ductal mucosa.
Early bile duct cancer; Direct peroral cholangioscopy; Narrow band imaging
Advanced esophageal adenocarcinomas arising from Barrett esophagus (BE) are tumors with an increasing incidence and poor prognosis. The aim of endoscopic surveillance of BE is to detect dysplasia, particularly high-grade dysplasia and intramucosal cancers that can subsequently be treated endoscopically before progression to invasive cancer with lymph node metastases. Current surveillance practice standards require the collection of random 4-quadrant biopsy specimens over every 1 to 2 cm of BE (Seattle protocol) to detect dysplasia with the assistance of white light endoscopy, in addition to performing targeted biopsies of recognizable lesions. This approach is labor-intensive but should currently be considered state of the art. Chromoendoscopy, virtual chromoendoscopy (e.g., narrow band imaging), and confocal laser endomicroscopy, in addition to high-definition standard endoscopy, might increase the diagnostic yield for the detection of dysplastic lesions. Until these modalities have been demonstrated to enhance efficiency or cost effectiveness, the standard protocol will remain careful examination using conventional off the shelf high-resolution endoscopes, combined with as longer inspection time which is associated with increased detection of dysplasia.
Barrett esophagus; Esophageal adenocarcinoma; Advanced imaging
Squamous cell carcinoma of the esophagus (SCCE) carries a poor prognosis due to late diagnosis. Early detection is highly desirable, since surgical and endoscopic resection offers the only possible cure for esophageal cancer. Population screening should be undertaken in high risk areas, and in low or moderate risk areas for people with risk factors (alcoholics, smokers, mate drinkers, history of head and neck cancer, achalasia and lye stricture of the esophagus). Esophageal balloon cytology is an easy and inexpensive sampling technique, but the current methods are insufficient for primary screening due to sampling errors. Conventional endoscopy with biopsy remains the standard procedure for the identification of pre-malignant and early malignant changes in esophageal mucosa and endoscopic detection. It may be enhanced by several techniques such as dye and optic chromoendoscopy, magnifying endoscopy, and optical-based spectroscopic and imaging modalities. Since more than 80% of SCCE deaths occur in developing countries, where expensive techniques such as narrow band imaging (NBI) and autofluorescence imaging are unavailable, the most cost-effective tool for targeting biopsies may be Lugol dye chromoendoscopy, since it is easy, accurate, inexpensive and available worldwide. In ideal conditions, or in developed countries, is it reasonable to think that optimal detection will require a combination of techniques, such as the combination of Lugol’s chromoendoscopy and NBI to identify esophageal areas that require further characterization by a high resolution technique. The efficacy and cost-effectiveness will determine whether these modalities will become part of standard endoscopy practice.
Autofluorescence endoscopy; Early diagnosis; Esophageal cancer; Esophageal squamous cell carcinoma; Lugol’s solution; Narrow-band imaging endoscopy
Endoscopic submucosal dissection (ESD) is the most advanced and representative technique in the field of therapeutic endoscopy and has been used for the treatment of gastrointestinal neoplasms, including early gastric cancer. The major difference and advantage of ESD compared to existing endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and polypectomy, are the width and depth of the resection. Newly developed cutting devices, distal attachable endoscopic accessories, and an advanced electrosurgical unit have helped to overcome the limitations of therapeutic endoscopy in terms of lesion size, location, presence of fibrotic scarring, and accompanying ulcers. As a result, the indications for ESD have been expanded from the classical indication for EMR and polypectomy, and there is now support for a further expansion of ESD indications. At present, the most critical factor to consider in the decision of whether to perform ESD is the probability of unexpected lymph node metastasis. The guidelines for ESD are continually being updated and debated. In this review, we discuss the strengths and weaknesses of the expanded guidelines, based on evidence found in the literature.
Endoscopic submucosal dissection; Endoscopic mucosal resection; Early gastric cancer; Indications