Pathology of the gastrointestinal tract can cause significant morbidity and mortality. Traditionally, endoscopy was used mostly to look for inflammation and causes of gastrointestinal bleeding. But bleeding is now less common and GI tract pathology is responsible for almost a quarter of all cancer deaths in Europe.1 Over the last few years, rapid advances have been made in endoscopic technologies to detect pre-malignant lesions and early cancer. These have led to minimally invasive endoscopic therapy with the potential of avoiding surgery.
This article will present an overview of the novel imaging techniques for virtual chromoendoscopy, in vivo histological diagnostics, new endoscope designs and novel therapeutics for managing premalignant and malignant disease.
Philipp Bozzini developed the first gastrointestinal endoscope in 1806 using artificial light, mirrors and a speculum. The first fibre optic endoscope appeared in 1957 and in the last 20 years, video endoscopy has become the standard of care. Image resolution continues to improve. Modern scopes use a Charge-Coupled Device (CCD) at the tip of the endoscope. Standard definition (SD) endoscope CCDs produce a resolution of up to 400,000 pixels whilst high definition (HD) endoscope CCDs produce images of 850,000 to 1.3 million pixels.
Magnification endoscopy (up to 150x magnification) allows greater visualisation of smaller areas of interest without loss of resolution.
Many endoscopy procedures are carried out to exclude cancer. Visualisation of subtle mucosal lesions can be enhanced with the application of dyes (such as acetic acid in Barrett’s oesophagus, Lugol’s iodine in oesophageal squamous dysplasia, methylene blue and indigo carmine for gastric and colonic lesions). The advent of virtual chromoendoscopy has reduced the need for these dyes through the manipulation of the white light images with either pre or postprocessing optical technologies to enhance the detection of small and subtle lesions that would otherwise be missed.
These techniques include proprietary imaging techniques including Olympus Narrow band imaging, Pentax i-Scan and i-Scan OE and Fuji Intelligent Colour Enhancement, which are summarised in Table 1. They have all been designed to be activated instantaneously by a simple switch on the endoscope hand piece, making them simple and very convenient to use.
Fig. 1: NBI of a colonic polyp with type IIIL Kudo Pitt Pattern. (With kind permission of Olympus).
Narrow band imaging
Narrow band imaging (NBI) mechanically filters the white light (400–700nm) to isolate blue (415nm) and green (540nm) light. These shorter wavelengths only penetrate the superficial layers of the mucosa. As a result of different absorptive and reflective properties of these wavelengths, an image that enhances superficial mucosa and vascular structures can be generated. Haemoglobin found in the capillaries appears darker. Changes in blood vessel patterns associated with pre-malignancy and early cancer are more easily observed using this system (Figure 1)
i-Scan and i-Scan OE
i-Scan utilises postprocessing technology to offer several modes of image enhancement. The modes available are summarised in Table 2 and representative images are shown in Figure 2. The latest development is to combine the postprocessing with a filtering ‘bandwidth-limiting’ technology similar to NBI. This is called i-scan Optical Enhancement (OE) and these imaging modes incorporate bandwidth-limiting light with digital image processing (Figure 3). The aim of this latest technology is to further enable the display of the surface structures of the blood vessels, glandular ducts and mucosal membranes in higher contrasts than white light.
Fig. 2: Pentax Images of an nodule in an area of Barrett’s mucosa using different i-scan modes.
Fig. 3: Images of an area of squamous mucosa with magnification using optical enhancement settings in a new Pentax OE system.
Fuji Intelligent Colour Enhancement (FICE) or optical band imaging limits the wavelength range of the light and offers images with brilliant colour and light quality. A proprietary algorithm makes it possible to select from a large number of wavelength combinations to alter the display of the mucosa depending on location and aim. In this way, FICE gives flexibility to formulate a diagnosis. The postprocessing technology converts images into individual wavelengths and reconstructs them to generate real time enhanced images.
All these technologies allow for greater detection of subtle lesions. They also require specialist expertise to recognise these abnormalities. Recent research has shown that a longer procedure time to allow a detailed inspection of the mucosa using high quality white light imaging may yield just as accurate diagnosis. Nonetheless, most expert endoscopists agree that these extra imaging modalities enhance their diagnostic toolkit.
Real-time in vivo diagnosis
Despite the application of dyes and the newer virtual chromoendoscopy technologies, none of the wide-field imaging approaches are good enough to completely replace histological conformation, nor is it expected that they ever will be.
Specialised technologies that aim to achieve in vivo diagnosis now exist. These have been developed as both point techniques for virtual histology and as wide-field techniques to examine the entire lumen of the organ in question. Technologies include confocal laser endomicroscopy, autofluorescence endoscopy and optical coherence tomography
Confocal laser endomicroscopy
Confocal laser endomicroscopy (CLE) is performed with a probe passed through the working channel of an endoscope (pCLE, Cellvizio; Mauna Kea Technologies, Paris, France). Focused infrared light is reflected through a pinhole and generates grey scale images once the tissue is made to fluoresce with topical or intravenous agents. High resolution of microstructures can be visualised in similar detail to histological sections. The probe can be used in the upper and lower gastrointestinal tract as well as the biliary tree and produces images with a resolution of less than 10 microns. This makes it possible to see individual cells as well as tissue architecture.
Autofluorescence (AF) is a virtual endoscopy technique utilising the variable quantities of fluorophores (substances that emit fluorescent light after exposure to short, blue light wavelengths). Alterations in the autofluorescence pattern of neoplastic tissue have been attributed to altered metabolic activity as well as haemoglobin content and a breakdown of collagen fibre cross-links.
This results in a shift toward the red spectrum when such tissue is excited with blue light. The altered autofluorescence signal is translated into false colour images, usually depicting neoplasia in purple against a green background of healthy mucosa. AF has been integrated with HD-WLE and NBI as part of the ‘endoscopic trimodal imaging’ (ETMI) system, although supporting evidence only exists currently for detection of early dysplasia in Barrett’s oesophagus and polyp differentiation in the colon.2,3
Molecular imaging can help identify disease-specific morphological or functional changes in individual cells with an altered molecular signature. Wheat germ agglutinin (lectin), once fluorescently conjugated, has been found to improve dysplastic lesion detection and opens a new discipline within endoscopic diagnostics.
Optical coherence tomography
Optical coherence tomography (OCT) uses reflected light in a manner similar to acoustic ultrasound to generate high resolution three-dimensional images. This allows ‘visualisation’ of the mucosa to a depth of 1–2mm. Currently performed with a probe through the working channel of an endoscope, the future may involve tethered capsule technology and rapid assessment of the tubular oesophagus.
New endoscope design
Whilst there have been impressive advances in imaging technologies there have also been many important developments in scope design.
Finding colonic polyps is crucial to the UK bowel cancer surveillance strategy as removal reduces the risk of colon cancer. Ensuring that the entire mucosa is visualised during colonoscopy is difficult due to the folds and flexures of the gastrointestinal tract and the forward viewing design of colonoscopes. Several novel devices are now available to improve visualisation. These include the Third Eye® Retroscope (Avantis Medical Systems, Sunnyvale, USA), which is placed through the working channel and allows retrograde viewing behind folds, improving adenoma detection rates in a multicentre trial.4
The G-EYE (Smart Medical, Ra’anana, Israel) colonoscope contains a built-in balloon on the endoscope shaft that, when inflated, can flatten folds and centralise the image. It also provides an anchor when performing therapeutic procedures. The G-EYE has also been shown to improve adenoma detection rates.5 Full spectrum view colonoscopy such as the The Fuse Full Spectrum Endoscopy® colonoscopy platform (EndoChoice Inc., Alpharetta, GA, USA), broadens the field of view from 170 degrees to 330 degrees (Figure 4) with a second viewing mode and improves adenoma
Fig. 4: The Fuse Full Spectrum Endoscopy colonoscopy platform permitting a wider field of view. (With kind permission of EndoChoice Inc).
Cholangioscopy allows visualisation of the biliary system, opening up novel diagnostic and therapeutic avenues. ‘Spyglass’ is a cholangioscope passed trough the working channel of a side-viewing duodenoscope that permits tissue sampling and therapeutic interventions for pancreato-biliary disease.
Transnasal endoscopy is performed through the nose with an ultra slim endoscope. It does not require sedation and is well tolerated, although risks include epistaxis and substandard histological specimens.7 In theory, this approach would be suited to an outpatient or office-based procedure, but for this to be successfully implemented, there is a need for a disposable system that does away with the need for endoscope cleaning between patients.
Small bowel capsule endoscopy is now part of routine care. New colon capsules allow visualisation of the colon without the need for full bowel preparation and include software to estimate polyp size. A drawback is the lack of real time therapeutic options including histological sampling and cleaning of areas of concern. Recently, a radio-controlled motor driven capsule that can change direction has been unveiled that may offer a more controlled examination of the gastrointestinal tract.
Historically, treatment for early gastrointestinal neoplasms required major surgery, with associated morbidity and mortality. Early neoplasms confined to the superficial layers of the mucosa and submucosa can now be treated endoscopically with minimal risk of nodal and metastatic spread.
Endoscopic mucosal resection
Endoscopic mucosal resection (EMR) is used to for the staging and treatment of superficial lesions and resection margins. The technique enables accurate histological assessment of the depth of invasion of early neoplastic lesions. There are several techniques to perform EMR including cap assisted, ligation assisted and injection assisted.
EMR is now part of the standard of care for early neoplasia in the oesophagus and stomach as well as for sessile polyps in the colon, which are becoming increasingly common.8
Radiofrequency ablation (RFA) (Covidien, Medtronic) is used to ablate the surface 500µm of the gastrointestinal mucosa. It is primarily used in the treatment of Barrett’s related neoplasia using a balloon (to provide a 360 degree ablation field) or a focal device, mounted over the endoscope (Figure 5). Several treatments are required to effectively treat Barrett’s oesophagus and any associated neoplasia. The treatment has a high success rates and good durability data now exist.9 Further indications may include treatment of gastrointestinal bleeding secondary to gastric antral vascular ectasia (‘watermelon stomach’) and radiation proctitis.10,11
Fig. 5: RFA of Barrett’s Oesophagus. Circumferential Barrett’s oesophagus prior to ablation (top left), placement of the 360 balloon catheter (top right) and following ablation (bottom left). Focal devices are also available (bottom right). (With kind permission of Medtronic).
Fig. 6: ESD of a gastric lesion.
Cryoablation utilises liquid nitrogen to form intracellular and extracellular ice that causes ischaemic necrosis on thawing and apoptosis of the treated cells. Limitations of cryotherapy include the large volume of gas that is produced during therapy, although a new focal balloon device avoids this (Cryoballoon Focal Ablation System (CbFAS), C2Therapeutics, USA) and has recently demonstrated squamous regeneration in the majority of patients treated for non-dysplastic Barrett’s oesophagus.12
Endoscopic submucosal dissection
In contrast to EMR, where large lesions may be removed piecemeal, endoscopic submucosal dissection (ESD) allows large lesions to be removed en bloc, as well as resection of tumours arising from the muscularis propria (Figure 6). ESD requires extensive training, longer procedure time and are associated with an increased risk of complications. The technique is most commonly used for gastric, and colonic cancers.13
POEM and NOTES
Per-oral endoscopic myotomy (POEM) is a novel approach for treatment of achalasia. The procedure involves the formation of a submucosal tract within the oesophagus before the lower oesophageal sphincter circular muscle fibres are cut (Figure 7). It offers a further option beyond endoscopic pneumatic dilatation and surgical Heller myotomy. This is one of a series of endoscopic techniques that may completely revolutionise surgery.
Further extension of the idea is developed through NOTES (natural orifice transluminal endoscopic surgery). This is an experimental ‘scarless’ surgical technique in which an endoscope is passed through a natural orifice such as the mouth or anus and then through an internal incision in the stomach or colon. It has been studied for use in appendicectomy and cholecystectomy. This field is likely to develop over the next few years.
Fig. 7: POEM demonstrating the formation of a submucosal tract (left), myotomy of the muscle fibres (centre) and closure of the submucosal tract (right).
Experience from bariatric surgery suggests that the proximal small bowel may play a role in the development of metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. Novel therapies to investigate this relationship and improve metabolic diseases are currently in trials and include the EndoBarrier® (GI Dynamics) and Revita™ duodenal mucosal resurfacing (Fractyl Labs).
Advances in technology have improved our detection of subtle abnormalities. With novel endoscopic design, previously unexplored areas of the gastrointestinal tract are now accessible and smaller endoscopes improve the patient experience. Newer modalities of treatment are also becoming available resulting in less invasive treatments and improved patient quality of life.
There are limits to the benefits technology can bring. Image quality relies on a stable scope position and minimal patient movement. Sedation and adequate procedure time is key to accurate diagnosis. Training is crucial for the endoscopist and histological confirmation of suspected cancer remains the gold standard.