Background: The main therapeutic modality of early upper gastrointestinal neoplasms has shifted from surgery to endoscopic therapy. The role of endoscopy has also expanded not only for more accurate diagnosis of neoplasms but also for the determination of extent and depth of neoplasms with a combination of multiple electronically modified images acquired with image-enhanced endoscopy (IEE) for assessing the feasibility of endoscopic treatment. Summary: These IEE with or without magnifying endoscopy including narrow-band imaging, blue laser imaging, and linked color imaging (LCI) using narrow-band light have greatly changed the diagnosis for upper gastrointestinal neoplasms. These modalities produce high color contrast between cancer and surrounding mucosa at distant views and clear visualization of surface and vessels at close-up observations. LCI shows purple color of intestinal metaplasia (IM) distinct from other inflammatory gastric mucosae and facilitates the recognition of early gastric cancers often surrounded by IM. Recently, ultrathin endoscopy has provided high-resolution images similar to standard-caliber endoscopy. In addition, these advanced IEEs that integrate computer-assisted artificial intelligence systems are marked and will improve our diagnostic performance for neoplasia in the future. Key Message: New IEE with sufficient brightness and color contrast has increasingly been used based on accumulated evidence for early and accurate detection of neoplastic lesions. We provide recent articles relevant to endoscopic diagnosis with IEE on esophageal, gastric, and duodenal neoplasms. Endoscopic equipment that integrates artificial intelligence support system is now being introduced into routine clinical use and is expected to enhance early detection of neoplastic lesions.

Until the early 2000s, the diagnosis of upper gastrointestinal (GI) neoplasms was performed only by white light imaging (WLI) using xenon light source. Gastric cancers often arise from the background mucosae with atrophic gastritis and intestinal metaplasia (IM) that are caused by Helicobacter pylori (H. pylori) infection in most cases. Thus, endoscopists have focused their attention on color changes of neoplasms such as redness and discoloration as well as morphological appearance including slight elevation or depression, which are not quite distinct from the surrounding mucosa with chronic inflammatory metaplastic changes. While early squamous cell neoplasms of esophagus and pharynx feature mainly flat appearance without ruggedness, only slight redness and disappearance of vessel structures are the findings suspicious of the presence of neoplasm.

WLI provides poor color tone even if morphological change exists in the lesion and surrounding mucosa, which makes it difficult to differentiate early GI cancers from inflammatory mucosa. Consequently, endoscopists, even experts, tend to overlook GI neoplasm if they solely use high resolution WLI.

Upper GI neoplasms were mainly treated by surgical resection until 1990s. In those days, endoscopy played a key role to detect cancer at early stages and obtain biopsy specimens, which depended on the training and experience of doctors. In the late 1990s through early 2000s, endoscopic submucosal dissection (ESD) was developed as a breakthrough-approach for endoscopic treatment. ESD enabled en bloc resection of tumors irrespective of the size or the presence of ulcer scar. Based on the frequency of lymph node metastasis, indication of ESD for early gastric cancer (EGC) has been proposed and expanded [1]. Currently, endoscopic therapy predominates over surgery for the treatment of EGC in Japan. Endoscopically curative resection is dependent on complete local excision and absence of lymph node metastasis. However, aforementioned endoscopic findings of EGCs are often subtle which makes precise delineation of the tumor margin difficult with WLI. Therefore, additional and detailed information enabling precise assessment on the extent and the depth of invasion of tumor are required to determine the lesions compatible with the indications of ESD. Endoscopic techniques such as magnifying endoscopy and image-enhanced endoscopy (IEE) have been developed to overcome these problems and are widely used now. In this review, we not only describe a recent progress in endoscopic diagnosis of gastric cancer but also cover early detection of the esophageal and duodenal neoplasms.

Magnifying Endoscopy

Magnifying endoscopy has a longer history than IEE. In the esophagus, for example, magnifying endoscopy without IEE identified the micro-vascular pattern of intrapapillary capillary loops (IPCLs) as a reliable indicator for tissue atypia of squamous cell epithelium [2, 3]. Subsequently, narrow-band imaging (NBI) was developed and allowed clearer visualization of IPCLs offering detailed information to judge the nature of the lesions. In particular, the degree of abnormal IPCL findings in the esophagus was correlated with the invasion depth of esophageal tumor [4]. In this way, IEE coupled with magnifying endoscopy dramatically changed endoscopic diagnosis of early esophageal squamous cell carcinoma (ESCC), which heralded their wider applications to other upper GI neoplasms such as intramucosal gastric carcinomas that exhibit only subtle changes in color and shape with conventional WLI [5].

Image-Enhanced Endoscopy

From 2000s, several modalities of IEE have been developed and improved to obtain better images which provided more information leading to precise diagnosis of GI neoplasms. Currently, available image-enhanced endoscopes with their features and advantages are listed in Table 1. To fulfill dual roles of endoscopic diagnosis, namely detecting neoplasms and qualitative evaluation of diseases including surrounding mucosae, application of IEE modalities according to the characteristics of organ such as lumen size and mucosal histology is mandatory. Different IEE modalities should be selected when screening upper GI tract depending on the lumen size of organs, i.e., narrow-lumen organs (pharynx, esophagus, duodenum) and wide-lumen organs (stomach). Endoscopists should be aware what organ-specific information is available using each modality. In particular, it is important to evaluate the mucosal features in detail because most of neoplasms are closely associated with inflammation in the background mucosa. Here, we describe characteristics and clinical use of each IEE.

Table 1.

Characteristic and advantage of IEE systems for upper GI tract

Screening (detection)Diagnosis: depth of invasionDiagnosis: lateral extension of tumorDiagnosis: benign or malignant
Esophagus BLI BLI BLI BLI 
NBI NBI NBI NBI 
LCI  Iodine staining Iodine staining 
Stomach LCI BLI BLI 
TXI  NBI NBI 
FICE  FICE  
Duodenum BLI 
   NBI 
Screening (detection)Diagnosis: depth of invasionDiagnosis: lateral extension of tumorDiagnosis: benign or malignant
Esophagus BLI BLI BLI BLI 
NBI NBI NBI NBI 
LCI  Iodine staining Iodine staining 
Stomach LCI BLI BLI 
TXI  NBI NBI 
FICE  FICE  
Duodenum BLI 
   NBI 

Narrow-Band Imaging

NBI, developed by Olympus Corporation, employed narrow-band light with the wavelengths of 415 nm and 530 nm which are absorbed by red blood cells and not reflected in the superficial layer to enhance the visibility of blood vessels against the background mucosa. Combined with a magnifying zoom, the accuracy of qualitative diagnosis on the extent and the invasion depth of superficial GI cancers has greatly improved. The improved visibility of blood vessels with magnifying endoscope enabled endoscopists to diagnose EGC combined with surface patterns simultaneously obtained [6]. In the esophagus, morphology of the IPCL and the accompanying avascular area have been used for the diagnosis of the depth of invasion [7]. However, first-generation NBI (EVIS SPECTRUM) without magnification was not suitable to observe target mucosa at a distant view due to insufficient light intensity. Therefore, it could be used for screening in the pharynx and esophagus with narrow lumens but not in the stomach with wider lumen. Moreover, no superiority in detecting polyps by the first NBI in tandem with WLI was reported in the colon with intermediate lumen size [8]. The second-generation NBI (EVIS ELITE) and the third-generation EVIS X1 are now on the market. In particular, it is noted that the illumination of EVIS X1 changed from xenon light to light-emitting diodes (LED). The amount of this light has increased by using all three RBG filters and thus endoscopists can observe the target mucosa at a distant view. In the stomach, a multicenter prospective study was reported that compared the ability to detect EGC between non-magnified WLI and non-magnified second-generation NBI [9]. Disappointedly, however, there was no difference in the performance between them although the positive predictive value of NBI was slightly superior to that of WLI. Future research is eagerly awaited if the 3rd generation EVIS X1 can be superior to conventional WLI in the detection of EGC.

Flexible Spectral Imaging Color Enhancement

Flexible spectral imaging color enhancement (FICE) using spectral imaging technology, which was conceived and marked by Fujifilm Corporation in 2006. The most important feature is that the image is bright. Therefore, the tumor can be observed with high color contrast to the surrounding mucosa even at a distant view, which is different from the image observed by NBI. FICE is useful to diagnose both depressed and elevated gastric cancers [10, 11] and is a pioneer of IEE in screening various lesions of the stomach with large lumen. In fact, the visibility of the demarcation line between EGC and the surrounding mucosa improved by nonexpert endoscopists and the color differences between malignant lesions and the surrounding mucosae were high even with ultrathin endoscopy [12], suggesting that FICE is potentially superior to WLI. However, it was not suitable for qualitative diagnosis of tumors because of the limitations in detailed observation of blood vessels even when used in combination with magnifying endoscopy.

Blue Laser Imaging

In 2012, LASERIO system was released by Fujifilm Corporation. This system changed the light source from xenon to laser light. WLI obtained by the laser endoscope is bright and clearly depicts the mucosal surface with/without magnification and is excellent to observe the fine structural images. Even WLI are fundamentally different between xenon light and laser light. The 450 nm laser light not only illuminates the observed mucosa but also produces white light from 400 to 700 nm through the phosphor. Furthermore, blue laser imaging (BLI) has a higher emission intensity at 410 nm, a shorter wavelength, and facilitates better visualization of microstructural and microvascular images. In addition, BLI produces high color contrast between lesions and surrounding mucosae at a near view, which results in advantages to detect malignant gastric lesions and to identify the demarcation lines. The 410 nm laser light is absorbed by the microvessels on the mucosal surface leading to clear visibility of the blood vessels whereas the 450 nm light facilitates to depict the fine structures of the surface layer [13]. In addition, another advantage is to obtain such microstructure and microvessels from low to high magnification. BLI image comprises not only spectral images by short wavelengths but also white light images and thus have thicker focus length leading to good focus easily obtained with various levels of magnification. Such simple techniques of magnification are feasible even with nonexpert endoscopists.

BLI-bright mode produces brighter image by adjusting the amount of white light component. Nevertheless, its brightness was insufficient for screening large-lumen organs such as the stomach. Both BLI and BLI-bright modes have sufficient light intensity in the antrum but insufficient in the gastric body. Recently, ELUXEO, which uses LED as the light source, was developed and generates white light and narrow-band short-wave light by controlling the luminescence intensity of the four-color LED lighting with high precision. Four colors comprise red, green, blue, and violet and the latter two form the image as a narrow band of wavelengths. BLI and BLI-bright images obtained from LED lights are similar to those from laser light. Endoscopic system using LED light has a long durability and uses less electric power and hence has an advantage in the costs. Therefore, this system will replace the laser imaging system and become a mainstream.

Linked Color Imaging

Recent advance of IEE for upper GI lesions sifted from magnifying observations of identified lesions to screening of entire organs. The diagnosis of gastric lesions needs much brighter images especially in the body and fornix. In 2014, Linked color imaging (LCI) mode was developed and originated from BLI-bright mode. Additional red component allowed brighter images of LCI enough to observe the entire stomach. Initially, LCI was developed for endoscopic diagnosis of gastritis and later was used to screen EGC [14, 15]. One of the advantages of LCI is that IM and gastric cancer are visualized as areas with different colors, purple and orange to red, respectively, which are easily distinguished. In detail, the blue-yellow dimension in the color space of Commission Internationale de l'éclairage has high value, which is the reason why the visibility of cancer is improved by LCI [16] because purple is made by mixing blue and red. Some flat gastric cancers have the similar color to the surrounding mucosa on WLL but with LCI, mucosal colors of these two areas become distinct. The diagnosis of gastric cancer has depended on abnormal morphological changes, which resulted in a considerable rate of missed diagnosis due to subtleness of the morphological alterations such as flat or minimum depression. LCI has opened up a new diagnostic era that such cancers could be identified as lesions with different colors prior to the morphological changes.

Texture and Color Enhancement Imaging

Texture and color enhancement imaging (TXI) was developed by Olympus Corporation and is a digital method IEE that optimizes and synthesizes WLI for each of the three elements of “structure: texture,” “color tone,” and “brightness.” In TXI, WLI is first divided into a texture image of unevenness information and a base image of brightness/color components, and subsequently these two images are synthesized and output after individual image processing (enhancement) (TXI mode 1). The structures, color tone, and brightness can be emphasized more appropriately by separating these three elements. TXI mode 2 enhances “structure: texture” and “brightness” except “color tone,” similar to mucosal color of WLI. Using TXI mode 2, endoscopists may not feel to observe the target mucosa obtained from IEE. The standard TXI mode 1 is expected to improve observation performance for lesions with subtle color changes [17]. The color difference between lesions and surrounding mucosa in the esophagus and stomach is reported to be improved [18, 19] and thus non-magnifying TXI has the possibility to pick-up and diagnose malignant lesions of upper GI tract. Currently, however, there is no solid evidence to support this expectation. IM is shown as purple (lavender color) using LCI but not with TXI. This difference may influence the diagnostic performance of TXI for EGC.

Painless Ultrathin Endoscopy as Screening Tool for Upper GI Lesions

Upper GI endoscopy has made a remarkable progress not only on higher resolution of images but on reducing procedural stress and discomfort. Standard oral endoscopy in awake accompanies gag reflex and pain which influence cardiopulmonary function and blood pressure. Also, oral endoscopy under anesthesia may cause hypotension, bradycardia, and respiratory suppression. Elderly patients with various cardiovascular diseases are increasing in the developed countries. Ultrathin endoscopy (≤6 mm diameter) may be appropriate for such patients as well as young adults susceptible to inducible gag reflex as it is less invasive due to insertion mainly through the transnasal route. It has been developed since the early 2000s and continuously improved during the last two decades. It is well tolerated without sedation because of minimal pain and gag reflex during the examination and is less costly [20, 21]. Ultrathin endoscopy via the transnasal route is considered a safer procedure with less adverse effect on the cardiopulmonary function of elderly patients including blood pressure and pulse rate [22]. Therefore, ultrathin endoscopy is used mainly in private clinics and for routine health evaluations in Japan. This painless endoscopy plays a role to prevent scattering of droplets caused by the gag reflex in the era of COVID-19. In the past, ultrathin endoscopy had poor image quality and both the sensitivity and specificity for diagnosing EGCs were significantly lower than that of high-resolution endoscopy, thereby many gastric lesions might be overlooked [23]. There is a trade-off between the resolution of images obtained and the smaller caliber endoscope. However, the diagnostic accuracy using ultrathin endoscopy combined with IEE has considerably been improved. The visibility of EGC by LCI using ultrathin endoscopes is superior to that by WLI using standard endoscopes with high resolution. Ultrathin endoscope (EG-L580NW) with LCI is also reported to have better sensitivity for EGCs than conventional endoscope (EG-L590WR) with WLI [24]. In the multicenter prospective trial, LCI is useful to identify neoplastic lesions for upper GI tract screening, even when used in ultrathin endoscopy [25]. In 2022, the ultrathin endoscope EG-840N with an LED light source was released, and it is equipped with a complementary metal oxide semiconductor [26]. This scope provides high resolution and detailed images of upper GI tracts and is expected to have better diagnostic performance for cancer screening.

Esophagus

Esophageal Squamous Cell Carcinoma

ESCC frequently develops from the background of inflamed esophagus in patients who had a history of heavy smoking, and alcohol drinking. Among drinkers, those with flushing reaction to alcohol have a much higher risk for ESCC. In WLI, diagnosis of ESCC is performed by picking up findings such as region of disappeared blood vessels, difference of color tone and fine mucosal irregularities obtained while inflating and deflating air. It is quite difficult, however, to identify the early stage of ESCC by WLI alone because these findings often escape detection. With NBI, early flat ESCC can be captured as a brownish area and the accuracy rate is higher than that with WLI [27]. Thus, IEE such as NBI and BLI is essential for screening the ESCC. Especially in elderly patients whose face turns red after drinking a small amount of alcohol (flasher), reflecting a deficient activity of acetaldehyde dehydrogenase type 2 (ALDH-2), there is a higher chance of detecting dysplasia [28].

The pink color sign obtained after iodine staining is useful for identifying esophageal neoplasms that should be treated. IEE combined with chromogenic endoscopy is also useful in distinguishing whether neoplasms require treatment [29]. Pink color of ESCC changes to more identifiable purple and green on LCI and BLI, respectively. These new colors produce high color contrast between ESCC and the surrounding mucosa, supported by objectively higher color difference [29]. These findings may be essential for the diagnosis of multiple iodine unstained lesions.

Using NBI or BLI, the diagnosis of invasion depth of ESCC has been established by altered morphology of the IPCL on the surface of the esophagus and contributed largely to the development of endoscopic treatment [7, 30]. IPCLs are classified into type A and type B. Type A vessels correspond to noncancerous lesions. Type B vessels are subclassified into B1, B2, and B3, corresponding to the diagnostic criteria for T1a-EP or T1a-LPM, T1a-MM or T1b-SM1, and T1b-SM2 tumors, respectively. These classifications (the JES classification) are widely used for the diagnosis of ESCC. The accuracy rate of IPCL is 90% for EP-LPM but about 60% for MM/SM1. The specificity of TypeB3 vessels is high [7].

Barrett’s Esophagus

It is important to determine the length of Barrett’s esophagus because longer Barrett’s mucosa increases the incidence of adenocarcinoma. Precise determination of the length, however, is hampered by the lack of reliable landmarks for the gastroesophageal junction. Palisade vessels, the relatively stable landmark for the gastroesophageal junction [31], are obscured by inflammation. Proximal end of gastric folds, another landmark often used by Western endoscopists is more susceptible to many factors, such as air insufflation and atrophic changes. Thus, endoscopic diagnosis of long, short, and even ultra-short segment Barrett’s esophagus had long been debated before the advent of IEE. IEE may help resolve the issue since palisade vessels can be more clearly visualized in Barrett’s esophagus mucosa with FICE [32] as well as LCI [33] than with WLI. Also, the demarcation between Barrett’s mucosa and upper end of gastric mucosa can be clearly identifiable. Greater color differences existed with FICE images between palisade vessels and background Barrett’s mucosa as well as between Barrett’s mucosa and gastric folds than with WLI, leading to better contrasting images. LCI shows purple palisade vessels clearly in the background mucosa. Also, purple palisade vessels are distinct from orange gastric mucosa. These images with high color contrast produced by LCI seem to be more useful for nonexpert endoscopists [33].

Esophageal Adenocarcinoma

Barrett’s esophageal adenocarcinoma is accompanied by inflammation due to mainly acid and bile reflux. It is difficult to evaluate this cancer and the background mucosa in detail solely with WLI. The prevalence of long-segment Barrett’s esophagus is rare in Japanese population and thus most of cancers occur in short segment Barrett’s esophagus. In Europe and the USA where the prevalence of long-segment Barrett’s esophagus is high, random biopsy in 4 directions every 2 cm is recommended for surveillance of Barrett’s esophagus and for screening Barrett’s adenocarcinoma according to the Seattle protocol [34]. While, in Japan, target biopsy based on precise diagnosis of suspicious lesions with IEE is recommended [35]. For this purpose, LCI and TXI are expected to be useful to detect such abnormal findings because these modalities emphasize color tone. Chromoendoscopy with spraying 1.5% acetic acid may also be useful for screening Barrett’s adenocarcinoma which is visualized as reddish areas due to the different rate of acid neutralization from the surrounding area [36]. However, this chemical staining requires an additional step and time. Barrett’s adenocarcinoma may accompany mild to severe inflammation in the surrounding mucosa. Endoscopic examination should be performed after improving inflammation by sufficient suppression of acid secretion.

Magnifying NBI and BLI are useful for qualitative diagnosis of Barrett’s adenocarcinoma. Accordingly, the Japanese Esophageal Society reported magnifying endoscopy classification of Barrett’s adenocarcinoma (JES-BE classification) [37]. When different mucosal patterns including size and shape of marginal crypt epithelium are found, the lesion is suspected as neoplastic. Subsequently, vascular pattern should be observed with high magnification. When the lesion exhibits an irregular vascular pattern, it should be diagnosed as neoplastic [37, 38]. The JES-BE diagnostic system has been reported to have a sensitivity of 87%, a specificity of 97%, a positive predictive value of 98%, a negative predictive value of 83%, and a diagnostic accuracy of 91% [37].

Stomach

Magnifying Endoscopy and IEE

It is well-known that early detection and treatment of gastric cancer improve the prognosis and minimize the impairment of quality of life of patients. To this end, endoscopic diagnosis using NBI and BLI with magnification has routinely been used in clinical practice. Microvascular and microsurface patterns (so-called VS classification) using these modes can facilitate determination of the demarcation line between gastric cancer and the surrounding mucosa to delineate the “cancerous lesion” exhibiting either irregular microvessel and/or irregular microsurface patterns [6, 39]. Diagnostic accuracy, sensitivity, and specificity of NBI are 90.4%, 60.0%, and 94.3%, respectively, for undiagnosed depressed lesions <10 mm in diameter identified by esophagogastroduodenoscopy. The accuracy and specificity of magnifying NBI were greater than those of conventional WLI [40]. Magnifying BLI and magnifying NBI have similar sensitivities of 96.1 and 98.1% for the demarcation line, 95.1 and 96.2% for irregular microvessel pattern, respectively, with no significant difference. However, irregular microsurface pattern with magnification was observed in 97.1% of lesions by BLI and 78.8% by NBL, respectively, with significant differences [41]. Thicker focus length of BLI enabled clear visualization of mucosal surface than that of NBI, which likely contributed to this difference.

It was reported that chromoendoscopy failed to delineate entire circumference in 18.9% of EGC lesions, but magnifying endoscopy with NBI could successfully detected with the entire margins in 72.6% of those lesions that had shown unclear margins using chromoendoscopy [42]. While, according to a multicenter randomized controlled trial, it was reported that the accurate rates of delineation of EGC lesions were similar between the magnifying NBI group and the chromoendoscopy group (88.0% and 85.7%, respectively) [43]. Nevertheless, it was reported that 10.5% of EGC were still missed with NBI magnifying endoscopy [44]. However, about 80% of them were H. pylori negative gastric cancers. No exposure of the tumor to the mucosal surface (gastric adenocarcinoma of fundic gland type and undifferentiated adenocarcinoma) and histological similarity with normal mucosa (well-differentiated adenocarcinoma with low-grade atypia) accounted for the major reasons for the false-negative diagnosis.

The extent of EGC was also evaluated by the setting of color enhancement of BLI. EGCs mainly appeared brown on BLI-bright or BLI. The surrounding mucosae were brown or pale green with C1 enhancement and dark green with C2 enhancement on BLI bright or BLI. The mucosa with greenish coloration with BLI corresponds to mainly histological IM (shown in Fig. 1). These differences of mucosal color between neoplasm and surrounding mucosae as supported by objective values of color difference provide distinct color contrast. The mean visibility scores by endoscopists for BLI-bright, BLI, and LCI with C2 enhancement were significantly higher than those with C1 enhancement. C2 color enhancement produced a significantly greater color difference between the malignant lesions and the surrounding mucosa [45]. Therefore, color enhancement settings are also important to determine the delineation of EGC. However, endoscopists tend to pay less attention to such setting of color enhancement in clinical use because BLI images in previously published articles failed to show color difference in the surrounding mucosa by C2 enhancement setting.

Fig. 1.

Early gastric cancer at the lesser curvature of the antrum (a) White light imaging shows slightly reddish mucosa, but it has similar color to the surrounding mucosa. b LCI shows orange red lesion suggestive of cancer, surrounded by purple non-cancerous mucosa. c White light imaging at close-up view. d LCI at close-up view. e BLI-bright mode with C1 color enhancement shows brown lesion surrounded by light green-brownish mucosa. f BLI-bright mode with C2 color enhancement shows brown lesion surrounded by greener mucosa although the difference between C1 and C2 enhancement is not much. g BLI with C1 color enhancement shows brown lesion surrounded by light brownish mucosa. h BLI with C2 color enhancement shows brown lesion surrounded by much greener mucosa. In contrast to the BLI-bright mode, BLI C2 enhancement produces obviously higher color contrast than BLI C1 enhancement. i White light imaging with CAD at a distant view. j LCI with CAD at a distant view. LCI delineates more precisely the extent of tumor than WLI. k White light imaging with CAD at close-up view. l LCI with CAD at close-up view. LCI discerns the tumorous lesion more precisely than WLI.

Fig. 1.

Early gastric cancer at the lesser curvature of the antrum (a) White light imaging shows slightly reddish mucosa, but it has similar color to the surrounding mucosa. b LCI shows orange red lesion suggestive of cancer, surrounded by purple non-cancerous mucosa. c White light imaging at close-up view. d LCI at close-up view. e BLI-bright mode with C1 color enhancement shows brown lesion surrounded by light green-brownish mucosa. f BLI-bright mode with C2 color enhancement shows brown lesion surrounded by greener mucosa although the difference between C1 and C2 enhancement is not much. g BLI with C1 color enhancement shows brown lesion surrounded by light brownish mucosa. h BLI with C2 color enhancement shows brown lesion surrounded by much greener mucosa. In contrast to the BLI-bright mode, BLI C2 enhancement produces obviously higher color contrast than BLI C1 enhancement. i White light imaging with CAD at a distant view. j LCI with CAD at a distant view. LCI delineates more precisely the extent of tumor than WLI. k White light imaging with CAD at close-up view. l LCI with CAD at close-up view. LCI discerns the tumorous lesion more precisely than WLI.

Close modal

Endoscopic Diagnosis of Gastritis

Chronic H. pylori infection predisposes atrophic gastritis often accompanied with IM, a precancerous condition. Therefore, precise endoscopic diagnosis of the infection is important to evaluate the risk of gastric cancer. LCI allows endoscopic diagnosis of H. pylori infection. “Diffuse redness” denotes uniform reddening of the entire fundic gland mucosa on WLI characterized by deep reddish-purple color on LCI. These findings suggest positive H. pylori status and are considered to reflect edema associated with inflammation. Conversely, in H. pylori-uninfected stomach, fundic gland mucosa exhibits “light orange color” without edema or IM [14]. After successful eradication, deep reddish-purple mucosa without atrophy or IM changes the color to light orange [46]. Therefore, it is desirable to observe the greater curvature of gastric body with less atrophy to diagnose H. pylori infection with LCI. The diagnostic accuracy of current H. pylori infection was significantly higher at 86.6% with LCI compared to 79.5% with WLI. Furthermore, LCI enables more accurate diagnosis of past H. pylori infection (LCI 78.9% vs. WLI 36.8%) [47].

IM is generally considered to be high risk for the development of gastric adenocarcinoma [48]. Despite of the importance of IM in this regard, endoscopists have faced difficulty in diagnosing it with WLI. Based on histological findings by biopsy samplings, the sensitivities of endoscopic diagnosis of IM with WLI are very poor, 12% in the antrum, 6% in the lesser curvature of corpus, and 13% in the greater curvature of corpus [49]. These data implied the requirement of new modalities in place of WLI to improve the endoscopic diagnosis of IM. In recent years, advantage of LCI in the diagnosis of IM has been well-documented [16, 50, 51]. For instance, diagnostic accuracies of IM by target biopsies were 23.7% on WLI and 84.2% on LCI by sampling the characteristic purple colored mucosa (lavender color sign) [50, 51]. We reported that 83% with purple mucosa and 17% with non-purple mucosa in areas of chronic gastritis were diagnosed as having IM by biopsy (83% accuracy) [16]. LCI produces much brighter images than WLI and thus can easily detect IM even at a distant view. Thus, LCI is instrumental in identifying not only IM itself but in detecting EGC often surrounded by IM (see the following section).

Screening for Early Gastric Cancer

Screening for the entire gastric mucosa requires sufficient brightness and high color contrast to ascertain visual distinction between lesions and the surrounding mucosa, which has impeded screening by NBI or BLI as compared to LCI to detect EGC. Using WLI, 74% of EGCs had similar colors to the surrounding mucosa [16], and therefore it is difficult to detect flat EGCs using WLI alone. In contrast, LCI can provide high color contrast between cancer and surrounding mucosa irrespective of morphological types including elevated, flat, and depressed lesions [52]. Why can LCI detect EGCs with completely flat form?

Two color patterns exist between EGC and the surrounding mucosa

  • 1.

    Orange EGC is surrounded by purple mucosa.

  • 2.

    Dark orange EGC is surrounded by light orange mucosa.

The color difference in LCI is significantly higher than in WLI. Among color component values of L*, a*, and b*, the yellow-blue component (b*) has high value between orange-red, orange or orange-white cancer and surrounding purple mucosa. This color pattern produces high color contrast and is very important to identify flat cancer easily even at distant view (Fig. 1) [16]. Therefore, the presence of purplish IM greatly contributes to color difference between cancer and the surrounding mucosa [52]. Light orange color in the surrounding mucosa is found in atrophic mucosa or no atrophic mucosa without H. pylori infection. Since EGCs have darker color than that of the surrounding mucosa, such color pattern is also helpful for their detection by LCI.

Khurelbaatar et al. [53] reported that 46.4% of EGC evaluated as poor visibility on WLI was changed to good visibility on LCI, while 4.9% of evaluated as good visibility on WLI was changed to poor visibility on LCI. According to the multivariate analysis, LCI contributed most strongly to good visibility of EGCs among various factors including tumor shape, depth of invasion, location, and H. pylori infection [53]. This implies that obscure EGC would easily be missed without LCI. H. pylori eradication made it difficult to detect EGC because of complicated background mucosa including atrophy, IM as well as normal surface mucosa covering cancer glands. However, LCI significantly improved the visibility of EGC compared with WLI even after eradication and decreased miss rates [54].

In clinical practice, a multicenter prospective study has already reported that the identification of neoplasms in the upper GI tracts is higher with LCI than with WLI [55]. WLI overlooked 41% of upper GI lesions whereas LCI did only 7%. Although there are a few weak points of LCI, endoscopists should recognize that screening examination using LCI is clearly superior to that using WLI, which brings beneficial effects for the patients with EGCs.

Can IEE Reduce Gastric Cancer Mortality?

As the results of recent multicenter prospective studies, it has been reported that the 5-year overall survival of EGC treated by endoscopic treatment is approximately 90%, and cancer-related death is only 0.1% [56]. Early detection undoubtedly leads to early treatment, while endoscopists need to recognize that monitoring for metachronous cancer is extremely important after endoscopic resection. Follow-up with IEE may also greatly contribute to early detection of these metachronous cancers.

It was reported that endoscopic screening can reduce mortality from gastric cancer by 57–67% compared with radiographic screening [57, 58]. However, there are no reports proving that direct use of IEE reduces mortality of gastric cancer. Perhaps, IEE is not used yet for gastric cancer screening program. Considering above-mentioned superiority of IEE, it is ideal to adopt IEE into EGC screening program. However, even in Japan where IEE is relatively widespread, it is not used at every hospital. This may be the reason why the usefulness of IEE has not been applied in the gastric screening program yet. In the future, we hope that IEE will not only improve the cancer detection rate but also help building solid evidence of reduced mortality of gastric cancer.

Mucosa-Associated Lymphoid Tissue Lymphoma

Endoscopic diagnosis of gastric mucosa-associated lymphoid tissue lymphoma (MALToma) is often difficult because of paucity of specific findings. Lymphoma cells sometimes distribute unevenly in the gastric mucosa. Therefore, even if MALToma is suspected by endoscopy, biopsy specimens may not lead to definite diagnose. However, NBI shows that the tree-like appearance is a characteristic finding of MALToma with magnification. This appearance may disappear after complete regression by H. pylori eradication [59]. BLI also shows similar appearance of MALToma with magnification. NBI or BLI magnifying endoscopy is useful not only in the diagnosis but also in the evaluation of the response to eradication therapy of gastric MALToma.

Duodenum

The incidence of superficial non-ampullary duodenal epithelial tumor is low in GI tumors and is a rare disease in clinical practice. However, duodenal tumors have been paid attention because they have been more frequently detected in H. pylori negative patients in Japan and are the second leading cause of death in patients who have familial adenomatous polyposis. Compared to other GI neoplasms, biopsy does not have high diagnostic performance prior to their endoscopic treatments. Furthermore, it might hinder endoscopic treatment [60], and hence prior biopsy sampling is not recommended. Embryologically, the duodenum consists of the foregut and the midgut at a border on the Papillae of Vater. Tumors with different mucus phenotypes exist on the oral and anal sides of the papillae. Gastric phenotype histologically correlates to malignant potential [61], and thus it is important to estimate the mucus phenotype in the duodenum before endoscopic treatment. White color change of the mucosa, “white milk mucosa,” reflecting fat absorption is an indicator of intestinal phenotype tumor located in the anal side of papilla. Duodenal cancer can be distinguished from non-cancer by the distribution of the white matter in the white-milk mucosa, and its lower deposition rate is associated with higher incidence of cancer [62].

In recent years, a diagnostic algorithm has been proposed that simply distinguishes cancer from non-cancer based on the combination of the white matter and mucosal structure using IEE with magnification. The surface structure comprises two types; open-loop defined as a linear mucosal structure and closed-loop as a circular, polygonal, or oval-shaped mucosal structure. In open-loop structure, the presence of white opaque substance is diagnosed as superficial duodenal epithelial tumor, while the absence is judged as non-neoplastic lesion. Closed-loop tumors with demarcation line are superficial duodenal epithelial tumor if there is no enlarged marginal epithelium (Fig. 2) [63].

Fig. 2.

Diagnostic algorithm to distinguish superficial duodenal epithelial tumor and non-neoplastic lesion (a) Open-loop structure defined as linear mucosal structures accompanies white opaque substance (WOS), suggesting superficial duodenal epithelial tumor (SDET). b No such features exist in the mucosa, which indicates non-neoplastic lesion (NNL). c Closed-loop structure with a circular or oval-shape does not accompany enlarged marginal epithelium (EME) with thicker white lines more than 2-folds compared with the background mucosa, suggesting SDET. d White closed-loop structure accompanies EME, suggesting NNL.

Fig. 2.

Diagnostic algorithm to distinguish superficial duodenal epithelial tumor and non-neoplastic lesion (a) Open-loop structure defined as linear mucosal structures accompanies white opaque substance (WOS), suggesting superficial duodenal epithelial tumor (SDET). b No such features exist in the mucosa, which indicates non-neoplastic lesion (NNL). c Closed-loop structure with a circular or oval-shape does not accompany enlarged marginal epithelium (EME) with thicker white lines more than 2-folds compared with the background mucosa, suggesting SDET. d White closed-loop structure accompanies EME, suggesting NNL.

Close modal

Both LCI and BLI are useful to evaluate a new type of duodenal tumor in detail. Sessile serrated lesions in the large intestine have a link to neoplastic pathway (serrated pathway). Recently, the first case with duodenal sessile serrated lesion was published and its endoscopic finding was described in detail using IEE. Magnifying BLI showed various-sized villous-like structures with dilated crypt openings in the white surface mucosa. Pathological findings of the resected specimen showed a saw-tooth structure corresponding to basal crypt dilatation and branching with mucus and positive immunostaining for MUC6 and MUC2, similar to a colonic sessile serrated lesion which has malignant potential. In this way, IEE may play a role for detailed evaluation of unknown diseases [64].

The artificial intelligence (AI) is known as the “ fourth industrial revolution” and is currently rapidly evolving combined with deep-learning technology, high-performance graphics-processing units, and large amounts of digitized data. Practical applications of AI in the medical field start from the “image diagnosis support” including computer tomography and plain X-p of lung and so forth. The use of computer-aided diagnosis (CAD) in GI endoscopic imaging is rapidly progressing due to development of the convolutional neural network. Recently, favorable qualitative and quantitative results using this network have been reported such as detection for gastric cancer [65], depth of its invasion [66], and distinction of malignancy from benign lesion by NBI [67]. In detail, AI system achieved high diagnostic accuracy in detecting upper GI cancers, exhibiting a sensitivity similar to that of expert endoscopists and surpassing that of non-expert endoscopists [68]. As for the background mucosa, the CAD using LCI is useful to evaluate H. pylori status [69]. The CAD using LCI has potential to facilitate detection of EGCs because it provides high color contrast between malignant lesion and surrounding area as well as visible mucosal structure and vessels.

Regarding ESCC, AI-based system is useful for its detection, differentiation from benign lesion [70, 71] and determination of invasive depth [72, 73]. IEE and magnifying endoscopes are essential for the development of CAD using AI.

Systematic review and meta-analysis were reported about AI-assisted endoscopic diagnosis of early upper GI cancer and showed extremely high sensitivity and specificity [74]. However, most AI-assisted diagnosis was performed using WLI despite a lot of literature indicated that IEE was superior to WLI for such diagnosis. In Japan, upper GI endoscopy systems which integrated CAD assistance to IEE (including LCI and BLI) have already been introduced in actual clinical practice since 2022 and the real-world evidence for their diagnostic performance will be accumulated in the near future.

Endoscopic diagnosis of neoplastic lesions has continuously been improved thanks to the remarkable technical progress of imaging technology. In recent years, the detection of lesions using IEE with sufficient brightness and color tone has gathered much attention because of the utility in surveillance or screening. Currently, the high-end endoscopy system with integrated CAD has already been introduced into market and will become more popular in the future. Nevertheless, endoscopists have to be the final judge whether lesion is benign or malignant requiring biopsy sampling and thus understand the basic characteristics, advantages, and weaknesses of each IEE and magnifying endoscopy.

We thank all the colleagues of our department for collaborating endoscopic examinations throughout this study. Special thanks to Professor Hironori Yamamoto for supporting the development of IEE.

Yoshimasa Miura has received honoraria from Fujifilm Corporation. Hiroyuki Osawa has a consultant relationship with the Fujifilm Corporation and has received honoraria, grants from the Fujifilm Corporation. Kentaro Sugano serves as an advisor of Fujifilm Corporation.

Authors have no funding sources about this review article.

Y.M. wrote the manuscript. H.O. and K.S. provided intellectual input and edited the manuscript.

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