23 Barrett’s Esophagus and Early Neoplasia
Maximilien Barret, Roos E. Pouw, Kamar Belghazi, and Jacques J. G. H. M. Bergman
23.1 Diagnostic Work-Up for Barrett’s Esophagus and Early Neoplasia
23.1.1 General Approach to Barrett’s Esophagus
Definitions of Barrett’s Esophagus
The diagnosis of Barrett’s esophagus (BE) requires the presence of endoscopically visible columnar mucosa in the tubular esophagus. There is no consensus if the presence of intestinal metaplasia (IM) in biopsies from the tubular esophagus is a prerequisite for the diagnosis of BE. Guidelines from the United States 1 require histologic confirmation of IM for the diagnosis of BE, whereas the British guidelines also accept a histologic finding of fundic- or cardia-type metaplasia. 2 , 3
All guidelines agree, however, that the presence of IM is the most important risk factor for an increased risk of esophageal adenocarcinoma (EAC) (▶Table 23.1), and only advise endoscopic surveillance for those cases where the presence of IM is confirmed.
Definition of Dysplasia and Early Cancer
Malignant progression in BE is thought to be a multistep process, with progressive grades of dysplasia and eventually invasive cancer. Grading of neoplasia is performed according to the Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) noninvasive low-grade neoplasia (low-grade dysplasia [LGD]), (4) noninvasive high-grade neoplasia (high-grade dysplasia [HGD], noninvasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma, or beyond). 9
Importantly, the assessment of dysplasia can be troubled by the presence of inflammatory changes in the epithelium; therefore, reflux esophagitis grade C or D should be controlled prior to biopsy, and repeat endoscopic assessment after proton pump inhibitor (PPI) therapy for 8 to 12 weeks is recommended. 1
Indefinite for dysplasia is not an intermediate step in the pathogenesis of EAC, but rather a temporary diagnosis used when the biopsies show some features of dysplasia, but when epithelial regeneration (inflammation, erosion) might account for the atypia. Close follow-up is recommended, with a repeat endoscopy after optimization of acid-suppressive medications for 3 to 6 months. If the “indefinite for dysplasia” diagnosis is confirmed on this examination, a surveillance interval of 12 months is recommended. 1
Endoscopic Classification of Barrett’s Esophagus and Early Neoplastic Lesions
Classification of Barrett’s Esophagus
To describe the endoscopic extent of BE, the Prague classification was developed and validated in 2006. 10 This classification reports the circumferential extent (C) and the maximal extent of the Barrett’s segment (M), measured from the upper end of the gastric folds (▶Fig. 23.1). For example, with the top of the gastric folds measured at 38 cm of the dental arcade, circumferential Barrett’s mucosa up to 36 cm, and Barrett’s tongues extending up to 33 cm, the BE segment will be reported as C2M5.The Prague classification uses the proximal extent of the gastric folds as the gastroesophageal (GE) junction landmark for the distal margin of the Barrett’s segment. However, the definition of the GE junction remains a matter of debate. Localizing the most proximal extent of the gastric folds can be affected by the distention of the distal esophagus and proximal stomach; for example, overinsufflation of a hiatal hernia may lead to overdiagnosis of BE. In Asia, endoscopists tend to define the GE junction at the distal extent of the palisade vessels, which are fine longitudinal veins located in superficial layers of the distal esophagus. 9 , 11 The working group that developed the Prague C&M criteria did consider the palisade vessels as an alternative landmark but found it not to be reliably assessable in most of the BE videos they used in the validation process. 10 In addition, studies have shown a poor interobserver agreement for determining the lower end of the palisade zone. Other studies have reported that its use is associated with a prevalence of BE greater than 15% in Japanese patients referred for standard endoscopy, a rate which virtually proves the low reliability of this landmark. 12 , 13
Irrespective of the definition of the GE junction, differentiating an irregular Z-line with small triangular extensions of gastric mucosa in the tubular esophagus from an ultrashort-segment BE (< 1cm), remains a challenge for the endoscopist. Three main studies have well demonstrated the extremely low risk of neoplastic progression of IM of such findings, varying from 0 to 1.5% per year for dysplasia 14 , 15 and 0.01% for cancer. 16 Finally, the most recent BE guidelines advise that columnar epithelium extending above the upper end of the gastric folds less than 1 cm should not be routinely biopsied. For those cases where the presence of IM is documented in these short segments, there is no indication for surveillance. 1 , 2 ,378
Classification of Early Barrett’s Neoplasia
The macroscopic appearance of lesions in the esophagus should be described using the Paris classification. 17 , 18 This classification is based on a Japanese classification of the gross types of superficial neoplastic lesions, describing the following types: polypoid (pediculated: type 0–Ip and sessile: type 0–Is), flat and slightly elevated (type 0–IIa), flat and level (type 0–IIb), flat and depressed (type 0–IIc), or excavated (type 0–III). Assessment of the macroscopic type may provide important information about the possibility of endoscopic treatment. The flat-type lesions are the most prevalent lesions in BE (▶Fig. 23.2). These lesions are associated with the most favorable infiltration depth and differentiation grade and can usually be managed endoscopically. Type 0–III lesions are always associated with deep submucosal infiltration and therefore not amenable for endoscopic treatment (Video 23.1). 19 Although strong data are lacking, most type 0–Is lesions are also invading into the deeper submucosal layers.
23.1.2 Endoscopic Imaging of Barrett’s Esophagus
Endoscopic Imaging Techniques
In recent years, several new imaging technologies have been developed with the expectation that their use would improve the detection of early neoplasia in BE. 20 However, standard white-light endoscopic (WLE) remains the most important technique to detect neoplastic lesions in BE. The development of high-definition (HD) endoscopy systems with integrated optical chromoendoscopy techniques has been the most important improvement in Barrett’s endoscopy over the last decade.
Chromoendoscopy uses vital staining, contrast staining, or reactive staining to improve endoscopic visualization of neoplastic lesions. Vital stains (e.g., methylene blue) are actively absorbed by the epithelium. Contrast stains (e.g., indigo carmine) accumulate in mucosal pits and grooves, highlighting the superficial mucosal architecture. Reactive stains (e.g., acetic acid) react with the epithelium to temporarily change its appearance (“acetic whitening”) thus highlighting the mucosal pattern. In addition, the earlier disappearance of the whitening in early neoplasia may also improve its detection. Early studies on the use of methylene blue suggested increased detection of early neoplasia, 21 yet a recent meta-analysis of nine studies showed that there is no incremental yield for methylene blue chromoendoscopy over standard WLE. 22 In a randomized crossover study, indigo carmine did not show any benefit in terms of detection over optical chromoendoscopy and both chromoendoscopy techniques did not increase the number of patients diagnosed with neoplasia over HD-WLE. 23 Acetic acid is a cheap agent that increases the contrast of the mucosal pattern, and recent publications have suggested that it may be of aid in the identification of early neoplasia. 24 , 25 , 26 However, other studies have questioned the additional value of acetic acid over HD-WLE 27 and properly designed crossover studies, such as for methylene blue and indigo carmine, are lacking (▶Fig. 23.3).
Optical chromoendoscopy techniques improve the visualization of mucosal morphology without the use of dyes. Preprocessing techniques optimize mucosal and vascular imaging by adjusting the wavelength composition of the excitation light, generally by mainly using blue light. Blue light, by its shorter wavelength, only penetrates superficially into the tissue and causes less scattering. In addition, blue light is highly absorbed by hemoglobin, resulting in optimal visualization of blood vessels. Examples are narrow-band imaging (NBI; Olympus, Tokyo, Japan), or blue laser imaging (BLI; Fujifilm, Tokyo, Japan).
Postprocessing techniques use normal white-light excitation and reprocessing of the reflected images by an appropriate algorithm. Examples are Fuji intelligent chromo endoscopy (FICE, Fujifilm, Sataima, Japan), or i-Scan (Pentax, Tokyo, Japan).
Most preprocessing optical chromoendoscopy techniques also incorporate some kind of postprocessing algorithm but their essential part is the adjusted excitation wavelength. Therefore, these techniques have superior resolution and brightness compared to postprocessing optical chromoendoscopy techniques.
Most studies on optical chromoendoscopy techniques in BE have used NBI, with only two small-sized studies involving i-Scan 28 or FICE. 29 BLI has only recently become available. Regular mucosal and vascular NBI patterns have been shown to correlate with nondysplastic BE, while irregular features are associated with early neoplasia. 23 Although optical chromoendoscopy may offer a more detailed inspection of the mucosal and vascular morphology than HD-WLE, clinical studies have not clearly demonstrated an additional value over HD-WLE for the detection of Barrett’s neoplasia. Most experts, however, agree that the use of optical chromoendoscopy is useful in the delineation of early neoplastic lesions prior to resection.
Autofluorescence imaging (AFI) is based on the principle that certain endogenous substances, such as nicotinamide adenine dinucleotide and collagen, emit light of longer wavelengths when excited with light of shorter wavelengths. Spectroscopy studies have shown that Barrett’s neoplasia has a different autofluorescence spectrum compared with nonneoplastic Barrett’s mucosa. 30 , 31 These findings led to the development of wide-field AFI as a “red flag” technique, 32 which was later integrated with HD-WLE and NBI into an “endoscopic trimodal imaging” (ETMI) system. 33 In uncontrolled ETMI studies, AFI increased the detection of early neoplasia, while NBI reduced the false-positive rate associated with AFI. 34 However, two subsequent randomized crossover trials that compared ETMI with standard-resolution WLE with Seattle protocol biopsies, failed to show the superiority of ETMI in detection of early neoplasia. 35 , 36 The use of a third-generation AFI system with a dual-band autofluorescence algorithm also showed disappointing results. 37 A critical review of the clinical impact of AFI showed that it had only limited value in identifying patients with neoplasia or detecting additional neoplastic lesions in patients already known to harbor a neoplastic lesion elsewhere in the BE. 38 AFI is barely used in clinical practice nowadays.
Confocal Laser Endomicroscopy
Confocal laser endomicroscopy (CLE) and probe-based CLE (pCLE) have the potential of providing real-time histologic data during endoscopy, using intravenous injection of fluorescein to enhance the vascular structures. This technique has the potential of providing real-time histologic data during endoscopy. CLE is currently only available with the pCLE system, since the integrated CLE (iCLE) endoscopy system by Pentax/Optiscan, which had the best resolution and frame rate, has been taken out of market. CLE allows for a reliable prediction of the presence of neoplasia on preselected still images of BE, 39 , 40 however, other studies have shown a lower sensitivity of only 68%. 41 The combination of pCLE with HD-WLE may increase the detection of early neoplasia compared to HD-WLE alone. 40 Theoretically, the possibility of sampling only suspicious areas on pCLE could reduce the number of random biopsies. 42 , 43 However, pCLE equipment is expensive and obtaining good-quality pCLE images is challenging. Given its limited scanning depth, there is no use for CLE in assessing invasion depth of neoplastic lesions. The use of CLE for follow-up after endoscopic therapy has been suggested, 44 however, controlled studies in this field are lacking. Finally, the whole concept of real-time histologic assessment during endoscopy is questionable: first, the negative predictive value of pCLE will never be high enough to withhold endoscopists from sampling an area that appears suspicious on HD-WLE; second, proceeding immediately with treatment of identified visible lesions in which pCLE confirms the diagnosis of neoplasia is restricted since generally patients need to receive information and provide consent before practicing an endoscopic resection; third, while diagnostic endoscopies can be performed in any hospital, therapeutic endoscopies should be referred to tertiary care centers, according to the guidelines. 1 Therefore, the wide-scale diffusion of pCLE in the evaluation of BE is unlikely. An optimal HD-WLE inspection allows the detection of most prevalent neoplastic lesions, to sample them for histology after which the patient is informed and referred for treatment. In the absence of morphologic abnormalities, future management of BE will probably consist of sampling the Barrett’s segment, either with biopsies or brush cytology, not to detect morphologic changes (as on the biopsy samples or pCLE) but to detect molecular markers associated with an increased risk of progression, well before any morphologic abnormalities detectable on histology (or pCLE) occur. 45
Optical Coherence Tomography
Optical coherence tomography (OCT) works analogous to ultrasound, utilizing light waves instead of sound waves to create two-dimensional images based on differences in optical scattering of tissue structures. OCT generates cross-sectional images of tissues in real-time with a resolution comparable to low-power microscopy. Volumetric laser endomicroscopy (VLE) utilizes second-generation OCT technology, which is incorporated in a novel system: Nvision VLE Imaging System (NinePoint Medical Inc., Cambridge, Massachusetts, United States). This system is capable of performing a circumferential scan of the esophagus, with a length of 6 cm and a depth of 3 mm, in just 90 seconds. Since VLE enables subsurface examination, this system has the potential to aid in early BE neoplasia detection during endoscopy. In the future, VLE might guide the endoscopist in targeting suspicious areas and avoid the need for random biopsies. In order to reach this aim, clear distinction of neoplasia in BE on VLE has to be possible. Currently, ongoing studies are developing VLE criteria and scoring systems for BE neoplasia for use in clinical practice. 46 , 47 Just like pCLE, VLE is currently far from guiding therapeutic interventions or withholding an endoscopist to biopsy a visible lesion. However, given its potential to scan the whole Barrett’s segment and by its deeper scanning depth, it may help targeting biopsies on dysplastic areas in the future.