ANGIOGENESIS IN SUPERFICIAL ESOPHAGEAL SQUAMOUS CELL CARCINOMA: MAGNIFYING ENDOSCOPIC OBSERVATION AND MOLECULAR ANALYSIS

Observations of esophageal squamous cell carcinoma using magnifying endoscopy have now been carried out extensively and, as a result, it has become clear that the morphology of the microvessels evident at the tumor surface reflects the depth of tumor invasion. In M1 and M2 cancer, the surface microvasculature reveals dilation and elongation of the intrapapillary capillary loops (IPCL). However, at this stage, some immature capillaries resembling IPCL also arise inside the tumor and, therefore, the view of the microvasculature should be described as one showing ‘intermixing of modified IPCL and IPCL‐like immature capillaries (IPCL‐like abnormal capillary)’. As cancer invades into the muscularis mucosa (M3 or deeper), an obviously dilated and irregularly branched tumor‐specific vasculature, more accurately described as ‘neovasculature’, can be observed. From our magnifying endoscopy observations and studies of the molecular profile of early esophageal cancer, we conclude that two major angiogenic steps exist in precancerous and M3 lesions in the early phase of cancer progression. In addition, it is now possible to study cell morphology using an endocytoscope with a much higher magnification (×400–×1000) than magnifying endoscopes currently on the market. The histology revealed in this way may reduce the need for conventional biopsy histology in the future.     

USEFULNESS OF MAGNIFYING ENDOSCOPY IN UPPER GASTROINTESTINAL TRACT: HISTORY AND RECENT STUDIES

Although clinical trials using magnifying optical endoscopy have been reported, magnifying endoscopies have been remarkably developed in the period of electronic endoscopy. Magnifying electronic endoscopies with 80 or 100‐fold magnification are used for routine endoscopic examination of upper gastrointestinal tract in Japan. Magnifying endoscopy is used to visualize the microstructure and microvascular architecture of gastrointestinal surface mucosa. Microsurface structure of the mucosa includes normal structure, changed structure by inflammation and biological response, and tumor‐specific structure. Microvascular architecture includes normal vascular system and tumor microvessels. Magnifying endoscopy is starting to play an important role in diagnosis of any upper gastrointestinal diseases by assessment of magnified observation. Magnifying endoscopy holds a great deal of promise in the near future because magnifying endoscopic observation is approaching optical biopsy.     

ENDOCYTOSCOPIC OBSERVATION OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA

The endocytoscopy system (ECS), adapted for clinical use in 2003, is an ultra‐high‐power magnifying endoscope that allows observations at the cell level. ECS is based on the technology of light‐contact microscopy. The most evident use of ECS is for real‐time, high‐resolution diagnosis of nuclear abnormalities, mainly in patients with esophageal cancer. Up to now, three different types of ECS have been available. This diagnostic tool makes it possible to omit histological examination of biopsy samples in approximately 84% of esophageal squamous cell carcinoma, as evidence for both an increase of cell density and nuclear abnormalities is considered to be convincing proof that a lesion is malignant. Here we describe the features of ECS and the background that led to its development, and review the published literature pertaining to the observation of esophageal neoplasms using ECS.     

MAGNIFYING ENDOSCOPIC FINDINGS OF THE SURFACE STRUCTURE OF NON‐CANCEROUS MUCOSA SURROUNDING DIFFERENTIATED AND UNDIFFERENTIATED GASTRIC CARCINOMA

Background: Several reports have described the usefulness of magnifying endoscopy in observing the surface structure in gastric neoplasia. The aim of the present study was to evaluate the characteristics of the surface structure of non‐cancerous mucosa surrounding gastric cancer. Methods: Sixty Japanese patients with early gastric cancer were enrolled in this study. We observed the non‐cancerous gastric mucosa surrounding gastric carcinoma by magnifying endoscopy and classified the magnified view into four patterns: (A) dotted; (B) short‐linear; (C) striped; and (D) granular, according to Sakaki's classification. Results: All patients were diagnosed as having Helicobacter pylori infection, and histological evaluation revealed 46 types of differentiated and 14 types of undifferentiated‐type gastric carcinomas. There were significant differences in the gender, age and endoscopic‐atrophic‐border scale between patients with these two types. In all, the surface structure at 240 points (4 points each in 60 patients) of non‐cancerous mucosa was observed by magnifying endoscopy. The prevalences of the surface patterns of the mucosa surrounding differentiated carcinoma were: A, 1.1%; B, 8.1%; C, 28.3%; D, 62.5%, and those of the mucosa surrounding undifferentiated carcinoma were: A, 8.9%; B, 73.2%; C, 14.3%; D, 3.6%. There were significant differences in the surface structure of the non‐cancerous mucosa surrounding differentiated and undifferentiated gastric carcinoma. Conclusion: The microsurface structure of the gastric mucosa surrounding gastric cancer lesions differed between patients with differentiated and undifferentiated gastric cancer. These findings are expected to be useful for the early detection of gastric carcinoma lesions or for the determination of extensions of carcinoma lesions.     

胃肠道原发恶性淋巴瘤的内镜诊断探讨

本文报告经手术及病理检查证实的胃肠道原发恶性淋巴瘤２０例，对其中１３例行内镜检查者作了较细致观察与记录。肿瘤形态呈隆起型４例，溃疡型５例，局部浸润型１例，弥漫型３例。内镜确诊率为１５．４％，确诊加疑诊率为５３．８％。文中重点讨论了本病胃镜、肠镜的表现特点及活检取材的方法，提出了早期诊断的必要性和可能性。     

DIFFERENTIAL DIAGNOSIS OF GASTRIC LESIONS BY MAGNIFYING ENDOSCOPY

We performed magnifying endoscopy for patients with suspected gastric diseases. Among these patients, 67 patients with early gastric cancer and 31 benign gastric diseases were enrolled in this study. The patients with early gastric cancer included 46 differentiated tubular adenocarcinoma (33 mucosal cancer, 13 submucosal cancer) and 21 non‐differentiated tubular adenocarcinoma (12 mucosal cancer, 9 submucosal cancer). The benign gastric lesions included 23 gastric ulcer or gastric ulcer scars, three gastritis, and five gastric adenomas. Small regular patterns were observed; 39% in differentiated adenocarcinoma, 5% in undifferentiated adenocarcinoma, and 19% in benign gastric diseases. Irregular patterns were observed 37%, 52%, and 6%. Lack of visible structure was observed 18%, 90%, and 10%. Abnormal vessels were observed 26%, 81%, and 16%. Small regular patterns were observed significantly more frequently in differentiated adenocarcinoma than in undifferentiated adenocarcinoma (P < 0.001). Lack of visible structure and Irregular patterns were observed significantly more frequently in undifferentiated adenocarcinoma than in differentiated adenocarcinoma (P < 0.001). In order to spread this useful endoscopy widely easy recognition of abnormality, histological backbone, and further technical developments in hardware and software should be required.     

肝硬变上消化道大出血病因的内镜诊断

肝硬变上消化道大出血患者６２例，出血后６小时～１周内行胃镜检查及硬化剂治疗。检查证实无食管胃底静脉曲张２例；胃及十二指肠球部明显糜烂１４例（２２．６％），胃和十二指肠球部溃疡６例（９．７％）。９例（１４．５％）为非静脉曲张性出血，７例（１１．３％）为双因素性出血，表明将肝硬变上消化道大出血一概推断为食管静脉曲张破裂出血是片面的。作者强调早期内镜检查和治疗的重要性。     

MAGNIFYING ENDOSCOPIC FINDINGS OF NON‐EROSIVE REFLUX DISEASE

Magnifying endoscopies have been remarkably developed to visualize the microstructure of gastrointestinal surface mucosa and mucosal vascularity. Close examination is necessary not only for colorectal tumors but also for upper gastrointestinal disease. Magnifying endoscopic observations for a change of capillary vessels in the esophageal epithelium was helpful to diagnose the invasive depth of squamous cell carcinoma. Magnifying endoscopic observations using narrow‐band imaging of capillary vessels in esophageal epithelium is useful for the diagnosis of non‐erosive reflux disease, which cannot be visualized by conventional endoscopy.     

MICROVASCULAR PATTERNS OF ESOPHAGEAL MICRO SQUAMOUS CELL CARCINOMA ON MAGNIFYING ENDOSCOPY

Background: Recently, esophageal microcancers have been frequently diagnosed and are receiving increasing attention as initial findings of cancer. We examined whether the clinicopathological features and microvascular patterns of esophageal microcancers on magnifying endoscopy are useful for diagnosis. Methods: Magnifying endoscopy was performed to examine the histopathological features of 55 esophageal cancers measuring ≤10 mm in diameter (34 small cancers, 16 microcancers, and five supermicrocancers). Results: Although some lesions were detected only on iodine staining, most were detected on conventional endoscopic examination. Most small cancers and microcancers were m1 or m2; some were m3 or sm2. Supermicrocancers were dysplasia or m1 cancer. As for the microvascular pattern, most m1 and m2 cancers showed type 3 vessels, while most submucosal cancers showed type 4 vessels. Conclusions: Microvascular patterns on magnifying endoscopy are useful for the differential diagnosis of benign and malignant esophageal cancers and for estimating the depth of tumor invasion. The shape of small lesions is often altered considerably by biopsy. Residual tumor may persist unless the basal layer of the lesion is included in biopsy specimens, even in microcancers. Consequently, endoscopic mucosal resection, without biopsy, is being performed in increasing numbers of patients with lesions suspected to be cancer on the basis of their microvascular patterns.     

AN ENDOSCOPIC AND MAGNIFYING ENDOSCOPIC STUDY OF ESOPHAGEAL CARDIAC GLAND: WHAT ROLE DOES ESOPHAGEAL CARDIAC GLAND PLAY AT THE ESOPHAGO‐GASTRIC JUNCTION?

The purpose of this study was to ascertain whether areas of yellow elevated change in the distal squamous epithelium represent esophageal cardiac gland and to further assess the features of the exposed esophageal cardiac gland in the magnified view. In addition, the relationship between the columnar‐lined esophagus, gastro‐esophageal reflux disease (GERD), reflux esophagitis, and H. pylori infection was also assessed. Fifty patients (28 men, 22 women; median age 61 years) underwent elective upper GI endoscopy. The distal margin of the squamo‐columnar junction was observed to ascertain whether a yellow elevated lesion was present. When such a lesion was observed, this area was studied using magnifying endoscopy with acetic acid and a biopsy specimen was taken. Furthermore, biopsy specimens of the cardia, antrum, and body were taken for biopsy specimen to check for the presence of carditis, gastritis, and H. pylori. Of 38 patients showing the yellow elevated change, all showed exposed columnar epithelium and 30 patients proved to have esophageal cardiac gland tissue in biopsy specimens. Of 31 patients with H. pylori infection, all had carditis and the yellow elevated lesion. Of 19 patients with a H. pylori‐negative normal stomach, none had carditis and seven patients had the yellow elevated change which was ascertained to be esophageal cardia by biopsy. The yellow elevated change at the distal squamo‐columnar junction was revealed to be esophageal cardiac gland and exposed esophageal cardiac gland was visible in all cases by magnifying endoscopy with acetic acid.     

Endocytoscopic observation for esophageal squamous cell carcinoma: can biopsy histology be omitted?

We examined whether endocytoscopic observation of esophageal squamous cell carcinoma can replace the histologic examination of biopsy specimens. In a basic investigation, we examined 57 iodine‐unstained areas in the resected specimens of the esophagus from 28 individuals. The endocytoscopic findings were graded from 0 to 3 in tandem with observations of the iodine staining. For endocytoscopic observation, we sprayed 1% methylene blue or toluidine blue as a vital dye on the surface of the esophageal mucosa, allowing 15–20 s for sufficient staining. One endoscopist observed the target lesions and decided their endocytoscopic type classification. Histological diagnoses were made by two pathologists who were unaware of the endoscopic findings. We then compared the endocytoscopic diagnosis and conventional histological diagnosis. In an in vivo investigation, we examined 71 lesions of esophageal squamous cell carcinoma. Two endoscopists diagnosed the type classification in consultation with a pathologist with regard to ‘nuclear density,’‘nuclear abnormality,’ and ‘whether biopsy histology could have been omitted on the basis of endocytoscopic findings.’ For the in vivo observation, we utilized XEC120U (higher magnification type [×1100]), XEC300F (lower magnification type [×450]), and XGIF‐Q260EC1 (lower magnification type [×450]) instruments. In the basic investigation, among the 11 areas classified as Type 1, 10 (91%) were category 1 by the Vienna classification. Among the 39 lesions classified as Type 3, 36 (92%) were category 4 or 5. The sensitivity of endocytoscopy for malignant lesions (Vienna classification categories 4 and 5) was 94.7%, if Type 3 was considered malignant. The specificity was 84.2% according to the same criteria. In the in vivo observation, two endoscopists diagnosed more than 90% of esophageal squamous cell carcinomas as neoplasms using each type of endocytoscope. With regard to nuclear density, the pathologist considered it to be increased in 98% of cases with the XEC120U, in 94% with the XEC300F, and in 93% with the XGIF‐Q260EC1. With regard to nuclear abnormality, the positivity rate was 90% with the XEC120U, 78% with the XEC300F, and 80% with the XGIF‐Q260EC1. As to whether or not biopsy histology examination was considered necessary, the pathologist made a ‘Yes’ judgment for 84% of cases observed with the XEC120U, 66% with the XEC300F, and 67% with the XGIF‐Q260EC1. Cancerous lesions diagnosed as Type 3 by both endoscopists using the XEC120U accounted for 46 (90.2%) of the 51 cases. Among these 46 cases, biopsy histology was considered unnecessary by the pathologist in 43 (93.5%). We believe that endocytoscopic observation has the potential to reduce the extent of histologic examination of biopsy specimens in cases corresponding to Types 1 and 3 of our classification.     

MAGNIFYING ENDOSCOPY WITH NARROW BAND IMAGING FOR EARLY DIFFERENTIATED GASTRIC ADENOCARCINOMA

We have been using magnifying endoscopy with narrow band imaging (NBI) to study early differentiated gastric adenocarcinomas and to assess the relationship between microvessel pattern, pit pattern and histological pattern. The magnified view of the cancerous area showed three types of pattern: (i) a mesh pattern, consisting of mesh‐like connected microvessels; (ii) a loop pattern, consisting of loop‐like microvessels that were not connected and had tubule‐like or villus‐like mucosal structures along them; and (iii) an interrupted pattern, consisting of interrupted thick or thin vessels without mucosal structures. The mesh type of microvascular pattern showed a round pit pattern in 88.9% of cases (32/36) and the loop type of microvascular pattern showed a non‐round pit pattern in 100% of cases. Among lesions that showed a mesh pattern or a loop pattern, 94.9% (56/59) were mucosal cancer and 5.1% (3/59) were submucosal cancer. However, 92.3% (12/13) of lesions that showed an interrupted pattern were submucosal differentiated adenocarcinoma and 7.7% (1/13) were mucosal differentiated adenocarcinoma. The present findings provide basic data on the characteristics of mucosal differentiated gastric adenocarcinoma revealed by magnifying endoscopy with NBI, as well as invasive changes such as submucosal invasion.     

MANAGEMENT OF OBSCURE GASTROINTESTINAL BLEEDING BASED ON THE CLASSIFICATION OF CAPSULE ENDOSCOPIC BLEEDING FINDINGS

Background: Double‐balloon endoscopy (DBE) and capsule endoscopy (CE) have been useful in managing obscure gastrointestinal bleeding (OGIB). However, DBE is invasive, complex and time‐consuming, therefore indications should probably be selective. The aim of this study was to evaluate the usefulness of the classification of the CE bleeding findings for determining the indications and timing of DBE in patients with OGIB. Methods: From February 2003 to January 2009, 123 patients with OGIB who underwent CE were included in this study. These CE findings were classified based on the bleeding source. Type CE‐I, II, III, IV and 0 indicate active bleeding, previous bleeding, lesions without active bleeding, a lesion outside of the small bowel, and no findings, respectively. We compared diagnostic yield and outcome between the classification and the findings of DBE or enteroclysis. Results: Comparisons of the positive findings rate with DBE or enteroclysis, the treatment rate and the rebleeding rate with the classification showed: CE‐Ia, 100% (6/6), 50% (3/6), 33.3% (2/6); Ib, 66.7% (4/6), 0% (0/6), 16.7% (1/6); IIa, 33.3% (1/3), 33.3% (1/3), 33.3% (1/3); IIb, 53.8% (7/13),15.4% (2/13), 30.8% (4/13); III, 100% (84/84), 9.5% (8/84), 8.3% (7/84); IV, 100% (2/2), 50% (1/2), 0% (0/2); and 0, 0% (0/9), 0% (0/9), 0% (0/9), respectively. Conclusions: The proportion of patients requiring treatment, the positive findings rate with DBE or enteroclysis and the rebleeding rates tended to be higher in the higher ranked classification types (CE‐I > II > III > IV > 0). These findings suggest that the classification can provide useful information on determining the indications and timing of DBE.     

NOVEL AUTOFLUORESCENCE VIDEOENDOSCOPY IMAGING SYSTEM FOR DIAGNOSIS OF CANCERS IN THE DIGESTIVE TRACT

An autofluorescence (AF) endoscopy system produces real‐time pseudocolor images from computation of detecting natural tissue fluorescence from endogenous fluorophores that is emitted by excitation light. The system could specify lesions including malignancies by difference in tissue fluorescence properties and reveal early stage neoplasia not detectable by conventional white light (WL) endoscopy. Image quality of the prior autofluorescence imaging systems including fiber‐optic endoscope was not feasible for general clinical use. The authors investigated the clinical utility of the novel videoendoscopy system using a combination of autofluorescence and reflection imaging (AFI) in diagnosis of cancers in the digestive tract. AFI represented early stage cancers in the digestive tract as purple or magenta areas in a green background. The undifferentiated type early gastric cancers in the fundic mucosa showed a unique pattern; green areas in a purple background. Ulcerations or inflammation caused over‐diagnosis in the AF observation. AFI could reveal flat or isochromatic extensions that were not evident in the WL images. Because the current system of AFI has limitations on resolution and accuracy comparing with chromoendoscopy, it has much to be improved for a good adjunct to standard WL videoendoscopy for diagnosing of early stage digestive tract cancers.     

CONTACT ULTRA‐HIGH MAGNIFYING ENDOSCOPY CAN DIFFERENTIATE SQUAMOUS CELL CARCINOMA FROM NON‐CANCEROUS SQUAMOUS CELLS IN THE ESOPHAGUS: TWO CASES OF SUPERFICIAL ESOPHAGEAL CARCINOMA

Endocytoscopy, a type of contact ultra‐high magnifying endoscopy, enables in vivo observation of cells in the gastrointestinal tract. To test its clinical relevance, endocytoscopy was conducted on ex vivo specimens from two cases of superficial esophageal carcinoma that were resected by endoscopic mucosal resection (EMR). Using a catheter‐type system with ×450 magnification, endocytoscopic observation was performed on small areas of cancerous and non‐cancerous squamous cells, which were subsequently retrieved for pathological examination on horizontal sections. In both cases, endocytoscopy identified non‐cancerous areas as cells with sparsely distributed round nuclei and a low nucleus‐cytoplasm (NC) ratio, which correlated well with histological sections. Similarly, the endocytoscopy correlated well with histological sections of cancerous areas and identified cells with densely distributed irregular nuclei with a high NC ratio. In conclusion, the high correlation between histological and endocytoscopic identification of cancerous and non‐cancerous lesions may enable endocytoscopic diagnosis that is of comparable accuracy to the current pathological methodology. A prospective in vivo study is required to confirm the evidence.     

CLINICAL INVESTIGATION OF UPPER GASTROINTESTINAL HEMORRHAGE AFTER PERCUTANEOUS ENDOSCOPIC GASTROSTOMY

Background: Upper gastrointestinal (GI) hemorrhage after percutaneous endoscopic gastrostomy (PEG) is sometimes reported as one of the serious complications. Our purpose was to clarify the cause of upper GI hemorrhage after PEG. Patients and Methods: We retrospectively investigated the causes of upper GI hemorrhage among a total of 416 patients out of 426 consecutive patients who underwent PEG in our institution, excluding 10 patients who showed upper GI tumors on PEG placement. Results: Among 17 patients who developed upper GI hemorrhage after PEG, three and four patients showed PEG tube placement and replacement‐related hemorrhage, respectively; these lesions were vascular or mucosal tears around the gastrostomy site. Ten patients experienced 12 episodes of upper GI hemorrhage during PEG tube feeding. The lesions showing bleeding were caused by reflux esophagitis (five patients), gastric ulcer (two patients), gastric erosion due to mucosal inclusion in the side hole of the internal bolster (two patients), and duodenal diverticular hemorrhage (one patient). Anticoagulants were administered in six patients, including four patients with replacement‐related hemorrhage and one patient each with reflux esophagitis and gastric ulcer. Conclusions: Reflux esophagitis was the most frequent reason for upper GI hemorrhage after PEG. The interruption of anticoagulants should be considered for the prevention of hemorrhage on the placement as well as replacement of a gastrostomy tube.     

MAGNIFICATION ENDOSCOPY IN THE UPPER GI TRACT

Magnification endoscopy in conjunction with chromoendoscopy provides additional valuable and detailed information with respect to mucosal morphology. The most promising indications include the depiction and staging of squamous cell cancer of the esophagus, the potential to identify neoplasia within Barrett's esophagus, and the demarcation of early gastric cancer. However, the exact role of magnification endoscopy for routine clinical practice is not yet determined and is currently under investigation     

ENDOSCOPIC SUBMUCOSAL DISSECTION FOR EARLY GASTRIC CANCER USING MAGNIFYING ENDOSCOPY WITH A COMBINATION OF NARROW BAND IMAGING AND ACETIC ACID INSTILLATION

Demarcation of early gastric cancers is sometimes unclear. Enhanced‐magnification endoscopy with acetic acid instillation and magnifying endoscopy with a narrow band imaging (NBI) system have been useful for recognition of demarcation of early gastric cancers. We report a patient with early gastric cancer who underwent a successful endoscopic submucosal dissection (ESD) by magnifying endoscopy with the combined use of NBI and acetic acid instillation. A 72‐year‐old man with early gastric cancer underwent ESD. Demarcation of the lesion was not clear, but magnifying endoscopy using the combination of NBI and acetic acid clearly revealed the demarcation. ESD was carried out after spots were marked circumferentially. We identified the positional relation between the demarcation and all markings. Resection of the lesion was on the outside of the markings. Histopathologically, the lesion was diagnosed as a well‐differentiated adenocarcinoma limited to the mucosa. The margins were carcinoma free. Magnifying endoscopy combining the use of NBI with acetic acid instillation is simple and helpful for identifying the demarcation of early gastric cancer. This method may be useful in increasing the rate of complete resection by ESD for early gastric cancer.     

上消化道大息肉的内镜处理──附189例（275颗）报告

本文报告我院十年间在内镜下治疗１８９例，２７５颗上消化道大息肉（息肉＞１０ｍｍ）。采用方法有单纯性圈套套切法；圈套套切加息肉基底部注射硬化剂法及特大息肉的分次切除法。本组除１例胃穿孔，２例术后大出血外，无其他严重并发症。本文讨论了镜下摘除上消化道大息肉的术前准备，术中注意事项、并发症及术后处理。讨论了上消化道大息肉内镜下摘除的必要性。     

A PROSPECTIVE ENDOSCOPIC STUDY OF THE EFFECT OF ORUDIS AND ORUVAIL ON THE UPPER GASTROINTESTINAL TRACT, IN PATIENTS WITH OSTEOARTHRITIS

The effect of ketoprofen, a nonsteroidal anti-inflammatory drug,was tested on the upper gastrointestinal tract (UGIT) in patientswith osteoarthritis. The drug was given in two forms; as simpleketoprofen (Orudis) and as a slow release preparation (Oruvail),when the drug was not released into the stomach, but into thesmall intestine. These formulations were compared with indomethacinfor endoscopically proven damage to the UGIT. Orudis and Oruvail produced similar damage to previously normalUGITs over 56 days; each formulation produced about a 50% incidenceof ulceration and inflammation. Indomethacin, by comparisonproduced less damage. The results suggested that the directaction of ketoprofen (barrier breaking effect) adds little tothe mechanism of gastric cytotoxicity of this drug, which maybe assumed to be predominantly caused by a systemic effect ofketoprofen on gastric cytoprotective mechanisms. KEY WORDS: Ketoprofen, Orudis, Oruvail, Endoscopy, Upper gastrointestinal tract, Cytoprotection.