Definition and Staging of Early Esophageal, Gastric and Colorectal Cancer

 

Nikolas Eleftheriadis, Haruhiro Inoue, Haruo Ikeda, Manabu Onimaru, Akira Yoshida, Roberta Maselli, Grace Santi, Shin-ei Kudo

 

Nikolas Eleftheriadis, Haruhiro Inoue, Haruo Ikeda, Manabu Onimaru, Akira Yoshida, Roberta Maselli, Grace Santi, Shin-ei Kudo, Digestive Disease Center, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo, Tsuzuki-ku, Yokohama 224-8503, Japan

Correspondence to: Nikolas Eleftheriadis, MD, Digestive Disease Center, Showa University, Northern Yokohama Hospital, 35-1 Chigasakichuo, Tsuzuki-ku, Yokohama, 224-8503 Japan.

Email: nikoseleftheriadis@yahoo.com

Telephone: +81-45-949-700                       

Received: May 8, 2014                 Revised: June 10, 2014

Accepted: June 12, 2014

Published online: July 18, 2014

 

ABSTRACT

Accurate diagnosis of gastrointestinal (GI) cancer in early stages, endoscopically showed as superficial noninvasive lesions, is the current optimal strategy for optional outcome. Superficial GI cancer is defined as both mucosal and submucosal cancer with or without lymph node metastases. Curability however, is related to the risk of lymph node metastases, which is the major factor related to long-term outcome. A concept of early GI cancer therefore is local lesion which has no risk of lymph node metastasis, while invasive cancer is a superficial cancer with lymph node metastases. According to retrospective studies from surgically rejected specimens of early stage GI cancer with extensive lymph dissection, the rate of lymph node metastases was very low in mucosal carcinomas, which are considered curable by endoscopic rejection alone, but much higher in cases of submucosal invasion. For deep mucosal and slightly submucosal carcinomas there are subtle but important organ specific differences with m3-sm1 esophageal carcinomas to have high risk of lymph node metastases (>20%) despite the superficial appearance, while for m3-sm1 gastric and colorectal lesions have low risk of lymph node metastases and should be also considered for endoscopic treatment. Accurately preoperative staging of GI cancer is the present difficulty in clinics, which is vitally important for choosing appropriate treatment method. Chromoendoscopy in combination with high-resolution, magnification endoscopy and narrow band imaging (NBI) system has been introduced in clinical setting in order to identify subtle GI lesions. The combination of all these techniques permitted real time accurate endoscopic diagnosis of early GI cancer. Moreover, in Japan they have already established standardized endoscopic classifications for staging early GI cancer, using combined macroscopic classification, chromoendoscopy and NBI magnification endoscopy Pit pattern classification is described for colorectal lesions for years. Using NBI magnification it has been established the IPCL pattern classification for early stage easophageal cancer, while for gastric and colorectal cancers there have been described specific NBI magnifying classifications. Based on these classifications a real-time, reliable endoscopic diagnosis of early GI cancer can be made.

 

© 2014 ACT. All rights reserved.

 

Key words: Early gastrointestinal cancer; Definition; Lymph node metastases; Staging

 

Eleftheriadis N, Inoue H, Ikeda H, Onimaru M, Yoshida A, Maselli R, Santi G, Kudo S. Definition and Staging of Early Esophageal, Gastric and Colorectal Cancer. Journal of Tumor 2014; 2(7): 161-178 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/775

 

INTRODUCTION

According to Paris[1] classification of superficial gastrointestinal (GI) lesions: in the esophagus, stomach and colon, neoplastic lesions of the digestive tract are called superficial at endoscopy, when the endoscopic appearance suggests either a small cancer or a noninvasive neoplastic lesion (dysplasia/adenoma), while WHO[2] defined superficial GI cancer as both mucosal and submucosal cancer with or without metastases[3-5]. Superficial tumors correspond to the T1 stage of the TNM[3-5] classification, in which invasion is limited to the mucosa and submucosa (Tables 1, 2 and 3)[3-5]. Superficial tumors are non-obstructive, usually are asymptomatic and often are detected as an incidental finding or by screening.

 

 

 

    The term superficial, however, is in some way confusing, because it is not directly related to histology or invasiveness of a GI cancer, but simply describes the endoscopic appearance of a lesion, which looks to be restricted to superficial layers of GI tract.

    Instead of the term superficial, more accurate and clinically useful should be the term early GI cancer, which suggests a curable disease and has been already used and defined in Japan for decades[3-5].

    Curability of early stage GI cancer is related to the risk of lymph node metastases, which is the major factor related to long-term outcome of the GI cancer[6,7]. A concept of early cancer therefore is local lesion which has no risk of lymph node metastasis.

    One of the major factors that found to be related to the risk of lymph node metastases is the depth of invasion (mucosal versus submucosal)[8]. Infiltration pattern B, C and vessel permeation (ly, v) are another independent risk factors for lymph node involvement.

 

Depth of invasion and risk of lymph node metastases

According to review studies from surgically rejected specimens of early stage GI cancer with extensive lymph dissection, the rate of lymph node metastases was very low in mucosal carcinomas, 2%-4% for gastric[8-11], 2% -3% for esophageal[12,13], and 0% for colorectal carcinomas[14-16], but much higher in cases of submucosal invasion; namely 14-20% for gastric[10,17], 37-53% for esophageal[12] and 3% -18% for colorectal carcinomas[14-16] (Tables 4, 5).

 

 

     Further subclassification of mucosal (m1-3) and submucosal (sm1-3) GI cancers, according to the depth of invasion (Figure 1), has been proposed in Japan, in order to select those patients with minimal risk of lymph node metastases, who would benefited from endoscopic treatment[2-4,18].

 

 

    This subclassification was possible, after review studies of mucosal and submucosal thickness in surgically rejected specimens from early stage esophageal, gastric and colonic cancer and subsequent division of the submucosal space into three equal parts[3,5,6,18].

    This precise subdivision into six layers has been proposed because the risk of nodal metastases increases from nil to high with the depth of invasion in the successive layers of the mucosa and submucosa and because they have already established endoscopic classification system for predicting the depth of invasion using combined macroscopic classification, chromoendoscopy and NBI magnification endoscopy and lately endocytoscopy[19-25]. The combination of all these techniques permitted the real time accurate endoscopic prediction of the depth of invasion for otherwise superficial lesions. This is important for precise definite treatment decision (endoscopic versus surgery). In Japan it has been already established treatment guidelines based on these classifications for GI superficial cancers[26,27]. The correspondence between depth of invasion and the most appropriate treatment is shown in table 6.

 

 

    Submucosal 1 (Sm1) GI carcinoma, was then defined, as carcinoma invading the upper one third of the submucosa and was estimated for esophageal cancer less than 200 m, (sm1 esophageal cancer)[6,18], for sm1 gastric cancer less than 300 m and less than 500 m for sm1 colon cancer, respectively[26,28,29].

    According to these sub classifications, in all types of GI cancer-esophageal, gastric and colorectal cancer- m1 and m2 GI carcinomas have no risk of lymph node metastasis and are considered curable by endoscopic rejection alone, while sm2-sm3 have high risk of lymph node metastasis (up to 49%)[3-6,32] and should be treated by surgery. (Table 5, Figures 2 A-C)[10,12,16,17]. Regarding m3 and sm1 subtypes and risk of lymph node metastases, there are subtle but important differences between the different GI organs, which are presented below. It is obvious therefore that the term superficial used in Paris classification[1] is not equal to the term early GI cancer used here, while detailed histological classification (mucosal versus submucosal) of early stage GI cancer is of great importance.

 

 

Esophageal cancer: Depth of Tumor Invasion (T)

Particularly, for esophageal squamous cell (SCC) carcinoma (figure 2A), up to 10% of m3 carcinomas and about 20% of sm1 esophageal SCC have lymph node metastasis and are not absolutely indicated for endoscopic treatment[5,35] (Table 7).

 

 

    In conclusion, in esophageal SCC, m1 and m2 lesions have no risk of lymph node metastases and are absolutely indicated for endoscopic treatment, while sm2-sm3 and the majority of m3 and sm1 have high risk of lymph node metastases and should be treated by surgery.

    Lately, some subtypes of m3-sm1 esophageal SCCs, which present specific narrow band imaging (NBI) pattern (IPCL-V3A pattern classification, Inoues classification[36]) (Figure 14), had no risk of lymph node metastases despite the superficial submucosal invasion and are also relative candidates for endoscopic rejection (endoscopic submucosal dissection). According to this data, early esophageal carcinoma is defined the superficial mucosal carcinoma with m1-m2 invasion and m3-sm1 subtype with IPCL-V3A NBI pattern classification[36].

    The type T1 of esophageal cancer [tumor confined to mucosa (M) or submucosa (SM), according to TNM classification2], was further divided into two groups: T1a (mucosal cancer) and T1b (submucosal cancer) (Table 1). The T1a was further subdivided into three groups: T1a-EP (carcinoma in situ, Tis), T1a-LPM (tumor invasion through the lamina propria mucosa) and T1a-MM (tumor invasion to the muscularis mucusae). The depth of invasion in the submucosa (T1b) is divided into 3 sections of equivalent thickness: superficial (SM1), middle (SM2) and deep (SM3) (Table 1).

The relation between macroscopic classification of type 0 esophageal SCC and depth of invasion is shown in table 8[27]. According to this multicenter analysis conducted in Japan, protruding type 0-Ip+Is and excavated type 0-III esophageal lesions had higher risk of deep submucosal invasion (79% and 84% respectively)[27]. 

 

 

Gastric cancer: Depth of Tumor Invasion (T)

In stomach, no risk of lymph node metastases was found for gastric m3, sm1 cancers, while sm2-sm3 lesions have high risk of lymph node metastases (>20%)[8-11,17]. (Table 5, figure 2B)[37].

    Especially for gastric cancer, a simplest two-grade classification (sm1 and sm2) in regard to the invasion depth has been proposed. Sm1 gastric cancer is defined as submucosal penetration less than 500m from muscularis mucosa and Sm2 as invasion of 500 m or more (Figure 3).

 

 

    Gotoda et al[29] in a large number of patients with early stage gastric cancer found that sm1 (<500 m) gastric lesions had lower risk of lymph node metastases and when they were combined with other independent risk factors such as (a) differentiated type; (b) size smaller than 30 mm and (c) absence of lymphatic-vascular involvement, no lymph node metastases were found in patients with sm1 (<500 m) submucosal gastric cancer[29]. 

    The two grade classification of the submucosal gastric cancer (sm1, sm2) is more practical and useful and it was adapted in TNM classification (JCGC[38]) (Table 9). The type T1 of gastric cancer (tumor confined to mucosa (M) or submucosa (SM), according to TNM classification[2]), was further subclassified into T1a (mucosal cancer) and T1b (submucosal cancer) and the T1b was further subclassified to SM1 or T1b1 (tumor invasion within 0.5 mm of muscularis mucusae) and SM2 or T2b2 (tumor invasion is 0.5 mm or more deep into the muscularis mucosae) (Table 2 and 9).

 

 

    This subclassification was imposed from the necessity to accurate distinguish endoscopically curable early gastric cancer. This subclassification was absolutely necessary in the era of endoscopic submucosal dissection (ESD) en block rejection of early GI cancer.

    Further clinical studies by Gotoda[31] and colleagues from large number of surgically treated patients with early stage gastric cancer, were able to identify additional groups of patients with no or lower risk of lymph node metastases than the risks of mortality from surgery[31].

    Except for the submucosal invasion depth, other risk factors such as tumor size, histological type and lymphatic-vascular involvement, were also found to be independently related to the risk of lymph node metastases in submucosal gastric cancer[29].

    Histologically well and moderately differentiated tubular adenocarcinoma and papillary adenocarcinoma were classified as differentiated histological type; poorly differentiated adenocarcinoma and signet-ring cell carcinoma were classified as undifferentiated histological type[39,29]. Regarding early gastric cancer tubular and papillary variants represent 50% and 30% respectively of cases. Signet ring cell carcinoma and poorly differentiated carcinoma represent 25% and 15% respectively and are usually depressed or ulcerated[2].

    Initial studies demonstrated, that undifferentiated mucosal gastric adenocarcinomas, even in absence of submucosal invasion, had higher probability of lymph node metastases (4.2%) compared with differentiated mucosal gastric carcinomas (0.4%) and are not absolutely considered for endoscopic treatment (EMR/ESD)[31,40,41].

    Subsequent studies, however, showed that other factors as well, such as tumor size, lymphatic invasion, depth of invasion and ulceration had predictive value on the risk of lymph node metastasis in undifferentiated gastric adenocarcinomas. Particularly, gastric tumor less than 20 mm in size, confined to the mucosa, without lymphatic invasion or ulceration had very low risk for lymph node metastases and could be considered for curative ESD resection[31,42,43]. Under these conditions endoscopic treatment is currently recommended for undifferentiated gastric adenocarcinomas (relative indication)[31,42-44] (Table 6, figure 4 and 5D).

 

 

    There are also cases of early signet cell gastric carcinoma that have been complete rejected by ESD, such as a case from the Showa University, Northern Yokohama Hospital, Japan shown in figure 4.

    Further clinical studies by Gotoda[31] and colleagues from large number of surgically treated patients with early stage gastric cancer, were able to identify additional groups of patients with no or lower risk of lymph node metastases than the risks of mortality from surgery[31].

    These results allowed the development of an expanded list of candidates with no risk of lymph node metastases, suitable for endoscopic resection for early gastric cancer, as shown in table 10. The rationale of this recommendations is based upon the knowledge that larger-size lesions or lesions with undifferentiated histology type are more likely to extend into the deep submucosal layer and thus have a higher risk of lymph node metastases[29-31,45].

 

 

    Moreover, according to study by Tsujitanui et al[45] early stage gastric cancer depressed type (0-IIc) of less than 1 cm in diameter and the elevated type (0-IIa) of less than 2 cm in diameter are suitable for endoscopic treatment (EMR/ESD) (Table 11 and figure 5).

 

 

    According to the results of this study, in superficial gastric cancer, elevated type of more than 3 cm (0-I) and depressed type of 1 to 3 cm in diameter (0-III) were related to high risk of lymph node metastases and should be treated surgically, while depressed type of less than 1cm in diameter (0-IIc) and the elevated type (0-IIa) of less than 2 cm in diameter are suitable for endoscopic treatment (EMR/ESD) (Tables 10 and 11).

 

 

    The presence of lymph node metastasis is the most important prognostic factor for superficial gastric cancer. Because radical surgery with lymph node dissection has provided an excellent therapeutic outcome in early stage gastric cancer, with 5-year survival rate after curative resection more than 90% including recent European studies[29], precise diagnosis (pick up) of early gastric cancer and accurate indications for local EMR/ESD rejection, are fundamental for optional curative outcome.

    As a result of this policy, in cases with superficial gastric cancer with one or more risk factors for lymph node metastases (Table 12), such as undifferentiated type, size larger than 2 cm, the presence of lymphatic/venous involvement, submucosal invasion and ulcerative change, gastrectomy with lymph node dissection is recommended and usually performed, although the gastric lesion can be complete removed by endoscopy[31,46].

 

 

    However, in similar cases with contraindications for major surgery due to comorbidities or advanced age combined ESD rejection for the gastric tumor with laparoscopic lymph node rejection has been reported to be efficacious, in small group of patients with early stage gastric cancer, with one or more factors for lymph node metastases[46]. Furthermore, ESD rejection does not preclude future surgery, if needed. In contrast precise assessment of the en block rejected specimen provide a complete biopsy, crucial for further treatment planning (Figures 6 and 7). In view of these evolutions, a strict schedule was adapted and proposed, according to the JCGC[38], for handling the endoscopical rejected ESD specimen.

 

 

Colorectal cancer: Depth of Tumor Invasion (T)

According to Japanese Classifications of Colorectal Cancers (JCCC)[5] the depth of tumor invasion for colorectal cancer is as follow (Table 3):

    M: Invasion confined to mucosa

    M: Invasion to submucosal

    MP: Invasion to muscularis propria

For parts of intestine that have serosa/visceral peritoneum

    SS: Invasion to subserosa

    SE: Invasion penetrating serosa

    SI: Direct invasion to adjacent organs or structures

For parts of intestine that do not have serosa/visceral peritoneum

    A: Invasion through muscularis propria into pericolic or perirectal tissues

    AI: Direct invasion to adjacent organs or structures

   In colorectal cancer except for the depth of invasion important factor for lymph node metastases is also the width of invasion (Figure 8).

 

 

    Submucosal colorectal cancers are divided into sm1, 2 and 3 according to depth of invasion, while sm1 lesions are further divided into sm1a, 1b and 1c, according to width of invasion as shown in figure 8[26]. When the width of the submucosal invasion is less than the half of the total width, as in sm1a sm1b lesions, there is no risk of lymph node metastases and they defined as slightly invasive submucosal cancers (SMs). Sm1c (submucosal invasion more than the half of the total width), sm2 and sm3 lesions show substantial proportion of lymph node metastases (approximately 10%) and are defined massively invasive submucosal cancers (SMm)[26]. According to this data early colorectal cancer is defined the m1-m3 mucosal and sm1a, sm1b submucosal carcinoma, while sm1c, sm2-sm3 are invasive cancer.

    In conclusion for colorectal cancer m3, sm1a and sm1b lesions had no risk of lymph node metastases and are indicated for endoscopic treatment only, while sm1c, sm2 and sm3 colorectal cancer has more than 10% risk of lymph node metastases and should be treated by surgery[26] (Tables 4, 5 and figure 2C).

    The relation between macroscopic classification and size of type 0 colorectal cancer and depth of invasion is shown in table 13. According to this Japanese data presented in Paris classification[1], protruded type 0-Ip+Is, superficial elevated and flat type 0-IIa+IIb colorectal lesions less than 15 mm have low risk of submucosal invasion (<8%), while size more than >20 mm the risk of submucosal invasion increased to more than 17%. Depressed type 0-IIc lesions are related with the higher risk of submucosal invasion even in small size (<5 mm)[47-49]. Type 0-IIc colorectal lesions with diameter of more than 5 mm have >40% risk of submucosal invasion[48]. Based on the results of these studies specific treatment guidelines have been recommended.

 

 

Definition of Superficial, Mucosal, Submucosal, Early GI cancer

According to the results of the above-mentioned studies, Superficial, Mucosal, Submucosal, Early GI cancer were defined as follow:

    Superficial GI cancer is defined both mucosal and submucosal cancer with or without metastases[3-5] and generally corresponds to T1sm of TNM classification[3-5] (Figures 2 A, B and C).

    Mucosal cancer is defined as cancer confined to mucosal layer and corresponds to intramucosal cancer, T1m, T1a. (Figure 2 A, B, C, tables 1, 2, 3).

    Submucosal cancer is defined as invasive cancer to submucosal layer and corresponds to T1sm, T1b (TNM classification[37], WHO[49]). (Figures 2 A, B, C and tables 1, 2, 3).

    As a consequence of the above-mentioned results, taking into account the organ specific differences of lymph node metastases organ specific definitions of early GI cancer are proposed:

    Early gastric cancer is defined as mucosal (m1-m3) or upper submucosal (sm1 <500 m) carcinoma without lymph node metastases and is corresponding to T1a and T1b1 of the TNM classification (Figure 6 A-C).

    Early esophageal cancer is defined as upper mucosal (m1, m2) carcinoma without lymph node metastases and is corresponding to T1a of the TNM classification.

    Early colorectal cancer is defined as mucosal (m1-m3) or slightly invasive submucosal (SMs=sm1a sm1b) carcinoma without lymph node metastases and is corresponding to T1a and T1b1 of the TNM classification.

    All these early GI cancers can curably be treated by endoscopic means (EMR or ESD).

    In contrast to early GI cancer, we would like to distinguish invasive superficial GI cancer from advanced GI cancer.

    Advanced GI cancer is a GI cancer invading the muscularis propria or deeper (corresponding to T2-T4 of Borrmanns macroscopic classification), in contrast:

    Invasive cancer is a superficial cancer with lymph node metastases, and organ specific definitions is as follow:

    Invasive gastric cancer is defined as deep submucosal (sm2 >500 m) carcinoma with lymph node metastases and is corresponding to T1b2 of the TNM classification (Figure 7 a-d).

    Invasive esophageal cancer is defined as deep mucosal (m3) carcinoma and submucosal cancer (Sm2-Sm3), with lymph node metastases, (no correspondence to TNM classification)

    Invasive colorectal cancer is defined as deep invasive submucosal (SMm=sm1c) carcinoma with lymph node metastases, (correspond to T1b2 of TNM classification)

 

General principles of preoperative staging of superficial GI neoplasms

Accurate preoperative staging of superficial GI neoplasms is the present difficulty in clinics, which is vitally important for choosing appropriate treatment method (endoscopic versus surgery). In the West, endoscopists tend to base treatment decisions largely on tumor size and location and on the histology of biopsy specimens. However, in Japan, endoscopists have found that endoscopic classification of a GI lesion can be an important determinant of treatment decision especially, when endoscopic therapy should be applied. The high burden of GI cancer in Japan, forced Japanese investigators to develop advanced imaging techniques for endoscopic detection of very early GI cancer. 

    Based on the knowledge of Japanese Society of Endoscopy, especially (JCGC, JSED, JSCCR)[3-5] an international group of endoscopists, surgeons and pathologists proposed the Paris endoscopic classification of superficial lesions of the esophagus, stomach, and colon (Paris 2002)[1].

    During the past two decades however, Japanese endoscopists had learnt unlike the western endoscopists, how to diagnose and endoscopically treat early stages GI neoplasia. This goal was achieved by the earlier use of technical progress, including high resolution magnifying endoscopes and enhanced imaging capabilities, such as narrow-band imaging (NBI) system and mainly by precise classification and treatment guidelines, including development guidelines for minimal invasive endoscopic treatments[53].

    Chromoendoscopy in combination with high-resolution, magnification endoscopy and enhanced imaging technology such as NBI system has been introduced in clinical setting in order to identify subtle lesions. These endoscopic advancements were initially studied at leading Japanese medical centers and resulted in precise endoscopic description, with accurate prediction of invasion depth and optional treatment decisions.

    In view of these evolutions, revision of Paris classification is urgent, in order to incorporate classifications based on the new imaging technologies.

 

Endoscopic detection and chromoendoscopy

Recent models of videoendoscopes meet the requirements for the acquisition of a high-quality digital image in terms of resolution, color reproduction, contrast, and structure enhancement. The primary step in diagnosis is to identify the presence of a mucosal area slightly discolored (more pale or more red), an irregular microvascular network, or a slight elevation or depression.

    The second step in diagnosis is based on chromoendoscopy, to help in the meticulous description of the lesion. Chromoendoscopy should be readily available and should be performed when a target lesion has been detected. The routine use of endoscopic dyes to improve the imaging of a focal lesion does not mean that a systematic application covering the entire mucosal surface must be performed in every case. Diffuse staining to increase the yield of detection has, however, been proposed in those at high risk of neoplasia (e.g., familial colorectal cancer or ulcerative colitis).

    A variety of agents have been proposed for chromoendoscopy. Iodine solution (1.5%-2%), a vital stain, is the basic agent used for the stratified squamous epithelium of the esophagus[54,55]. Neoplastic areas remain unstained (negative stain), in contrast to the dark brown positive stain of the normal epithelium.

    The dye most commonly used on abnormal areas of the stomach and the colon is indigo carmine solution (0.5%-1%), a contrast stain. Chromoendoscopy with indigo carmine helps in the distinction between non-neoplastic (hyperplastic) or neoplastic lesions in the large bowel. Indigo carmine dye spraying, which is practiced routinely in Japan[56,57], has been also used in the West[58-62] but is still uncommon[63].

    Methylene blue chromoendoscopy has been used for the detection of intestinal metaplasia in the esophagus and the stomach and has been used in the large bowel by spraying a 0.1% solution in successive segments[64-69]. In a recent randomized study, this procedure was applied to the surveillance of patients with ulcerative colitis[70].

   An increased yield of non-polypoid neoplastic lesions was obtained in the group of patients evaluated with chromoendoscopy with magnification endoscopy[70]. Magnification optics were believed to be a major factor of improved efficacy[71]. The endoscopic application of dilute acetic acid has been proposed as a useful agent in studying the architecture of the metaplastic mucosa in Barretts esophagus[72,73] and lately in evaluation of early gastric cancer in combination with NBI magnifying endoscopy[74].

 

Organ specific endoscopic classifications of early GI cancer

NBI magnifying esophagoscopy and IPCL pattern classification of early esophageal cancer

Magnification endoscopy combined with NBI constitutes a novel advanced imaging technology, which enhances microvascular architecture of the superficial esophageal mucosa and permits real-time, accurate diagnosis of superficial malignant and premalignant esophageal lesions[75].

    Stratified squamous esophageal epithelium has no pit pattern, which is routinely observed in glandular epithelium of stomach and colon, instead a specific superficial capillary pattern, the Intra-epithelial Papillary Capillary Loop (IPCL), is identified[36,76,77] (Figure 9). The IPCL, which rises perpendicularly from the branching vessel, is barely recognizable under conventional endoscopy. By using the magnifying scope, which has magnification capability up to 80 times, the IPCL of the normal mucosa is identified as red dots.

 

 

    NBI enables more vivid observation of the IPCL. Branching vessels which are located at the relatively deeper layer are observed as green, and IPCL which is located at more superficial layer, is observed as brown loops (brown dots)[76,78,79]. In esophagus due to relatively narrow lumen, there is sufficient light to perform a complete visual survey of the mucosa under NBI imaging system.

    In Japan, as NBI imaging highlights better superficial malignant and premalignant esophageal lesions than white light endoscopy, it is routine to begin the diagnostic examination in esophagus with NBI with low optical magnification[77]. In the esophagus and pharynx, due to relatively narrow lumen, there is sufficient light to perform a complete visual survey of the mucosa under NBI. Any suspicious area is initially visualized as brownish area under NBI with low magnification and is further evaluated with NBI high magnification in combination with iodine (Lugol) chromoendoscopy.

    All suspicious brownish areas in esophagus are assessed with NBI high magnification endoscopy (¡Á80), in order to detect characteristic changes of IPCL pattern, which are directly related to tissue atypism and cancer invasion depth[36,76,77]. Switch from NBI to white light technique is easy accomplished just by pushing a button on the top of the handle of the endoscope.

    In superficial squamous cell esophageal carcinoma (SCC), four main characteristic changes of IPCL pattern have been detailed described (Figure 9)[80]: (a) Dilation; (b) Tortuosity; (c) Caliber change in a single IPCL and (d) Variation in the shape (uneven form) in multiple IPCLs.

    Based on these changes, IPCL pattern classification[36,75] systems of NBI magnifying findings have been described in order to demonstrate the tissue characterization for flat lesions (cancer versus non-cancer) and to predict the depth of invasion[36,81-83,75,77,84] (Figure 10). According to IPCL pattern classification, accurate selection of patients with early esophageal cancer for endoscopic (EMR/ESD) versus surgical treatment can be accomplished[36,76,77,80].

    The IPCL pattern classification includes two sets of diagnostic criteria. IPCL pattern classification from IPCL type I to Type V-1 (Figure 10) demonstrates the tissue characterization for flat lesion (normal to mucosal cancer), while IPCL pattern classification from type V-1 to type VN reflects cancer infiltration depth (m1, m2, m3 Sm1 to Sm2) (Figures 10-14).

 

 

 

 

 

    The IPCL pattern is categorized from type I (normal mucosa) to type V (carcinoma) (Figures 10,12 and 13):

      IPCL Type I: corresponds to normal mucosa.

    IPCL Type II: is often equivalent to regenerative tissue or inflammation.

    IPCL type III: is a borderline lesion which potentially includes esophagitis, but is often related to low-grade intraepithelial neoplasia (category 3 in revised Vienna classification[85]) (table 14). IPCL type III should be considered for further follow-up.

 

 

    IPCL Type IV: is equivalent to high-grade intraepithelial neoplasia or carcinoma in situ (category 4.1 and 4.2 revised Vienna classification85).

      IPCL Type V1: represent mucosal cancer (m1).

    IPCL Type V2: represent mucosal cancer (m2) (category 4.4 revised Vienna classification[85]).

     Local endoscopic treatment with EMR/ESD should be considered for IPCL type IV, type V-1 and type V-2, which definitely represent Tis and mucosal cancer m1 or m2, with no risk of lymph node metastases.

      IPCL Type V3 is subdivided into (Figure 14):

      IPCL Type V3A: corresponds to non invasive mucosal cancer, m2 (category 4.4 revised Vienna classification[85]) which is considered for endoscopic treatment (ESD).

    IPCL Type V3B: is referred to deep mucosal cancer m3 with submucosal invasion (Sm1) (category 5 revised Vienna classification[85]), which should be considered for surgery as there is increase risk of lymph node metastases[36,76,77].

    IPCL Type VN corresponds to new tumor vessel, which is cancer often associated with deeper invasion (sm2 or more) with significant risk of lymph node metastases and the surgical treatment should be recommended[76].

    The above-mentioned IPCL pattern classification has been also used for detecting and evaluating suspected superficial pharyngeal lesions and has been found reliable and accurate method in guiding endoscopic rejection for pharyngeal cancer as well[77,81,86]. In the oropharyngeal area chromo-endoscopy is not possible and NBI imaging provides a virtual chromoendoscopy with real time optical diagnosis.

    NBI magnification endoscopy in esophagus can be combined with chromo-endoscopy using iodine (Lugol) stain upon indication, which remains the best sensitive simple method for identification and precise delineation of squamous cell intraepithelial neoplasia or early cancer in esophagus[87]. Lugol chromoendoscopy in squamous cell epithelium reveals the pink color sign in the non-iodine-stained lesions, which confirms the existence of carcinoma or high-grade dysplasia. The pink color sign is recognized with NBI system as shiny silver sign. Combination of both phenomena is called pink-silver sign[88] (Figure 15). Shiny silver sing starts appearing around seven minutes after iodine staining. This process will be shortened by spraying of sodium thiosulfate solution, immediately after iodine staining[76]. However, NBI magnification imaging is superior to iodine crhomoendoscopy in detecting the depth of invasion and defining the endoscopic respectability of superficial early esophageal cancer.

 

 

NBI magnification imaging technique has been extensively studied with promising results in evaluating esophageal early SCCs, while the IPCL pattern classification has been proved reliable and accurate method for exact diagnosis and treatment decision of esophageal superficial SCCs[36,75-77]. NBI magnification imaging system has been proved superior to conventional white light endoscopy in detection of early, even minute <2 mm, esophageal SCC[76,78,79]. 

 

NBI magnifying endoscopic classification of early gastric cancer

NBI magnification endoscopy in stomach enhances both the microvascular architecture and microsurface structure of the superficial gastric mucosa, revealing specific NBI patterns and based on these findings a real-time, reliable endoscopic diagnosis of early gastric cancer can be made, according to several reports[82,89-91].

    Although there are no consistent guidelines for NBI magnification endoscopy for early gastric cancer, there are specific NBI classifications for gastric lesions, described in the literature[90,91]. Yao et al[90] first reported the VS classification (V=vascular pattern, S=surface pattern) and concluded that based on NBI magnification the major characteristic of early gastric cancer is the presence of a demarcation line with either irregular microvascular or irregular microsurface pattern[90].

    Furthermore, specific NBI magnifying findings of early gastric cancer are useful in predicting the histological type. Particularly, differentiated type adenocarcinomas are characterized by disappearance of regular subepithelial capillary network (SECN), a demarcation line and irregular-microvascular pattern (IMVP), while undifferentiated-type adenocarcinoma is characterized by a reduced microvascular pattern[90].

    Yokoyama et al[91] recently described a four pattern standardized classification- fine network (FNP), intralobular loop 1 (ILL1), intralobular loop 2 (ILL-2) and corkscrew (CSP) system patterns - (Figure 16) of NBI magnifying examination of early gastric cancer, which will be able to predict the histological subtype of most gastric carcinomas.

 

 

    According to Yokoyama et al[91] differentiated-type adenocarcinomas mainly showed FNP or ILL pattern, with more than 80% of differentiated type adenocarcinomas were classified as ILL-1 or less ILL-2. Undifferentiated-type adenocarcinomas were all classified as ILL-2 or CSP. These findings are of great significance for treatment decision as differentiated early gastric cancer is good candidate for endoscopic removal, while undifferentiated gastric cancer may be invasive cancer.

    Recently, acetic acid spray further emphasized the superficial gastric mucosal glandular structures and enhances the NBI magnifying endoscopic findings of early gastric cancer, revealing specific abnormal endoscopic patterns, such as small pit pattern, irregular villous pattern, or distorted pit pattern with absence of glandular structures (Figure 17)[74].

 

 

    Acetic acid spray enhanced the accuracy of NBI magnification endoscopy in differentiating malignant from benign superficial gastric lesions, especially in controversial cases. A novel four-type NBI magnifying endoscopic classification after acetic acid spray for early gastric cancer is also published[74].

Up to now NBI imaging in combination with high resolution magnifying endoscopy is the acceptable accurate method of choice for the preoperative evaluation of superficial gastric lesions.

 

Pit pattern and NBI magnifying endoscopic classification of early colorectal cancer

Colorectal lesions are classified according to modified Japanese classification of colorectal neoplasia[92] and Paris endoscopic classification of early GI cancer[1] by configuration, as depressed type (0-IIc), protruded type (0-Ip, 0-Isp, 0-Is) and flat type (0-IIa)[92,93] (Figure 18).

 

 

    Some elevated colorectal lesions may reach a large (>10mm) lateral diameter without increasing in their height or protrusion above the mucosa. These are called Lateral Spreading Tumors (LST) and they tend to have a rather benign nature despite their large size. Laterally spreading colorectal tumors were divided into subgroups and are expressed as 0-IIa, 0-IIc+IIa, or 0-IIa+Is, according to the categories of the Paris classification[1].

    Magnification colonoscopy enabled in vivo visualization of the fine surface microstructure of various colorectal lesions, while the combination of chromoendoscopy with magnifying colonoscopy is useful for detecting small localized lesions, for differential diagnosis and for determining not only the lateral extent but also the depth of a lesion.

    Pit pattern is the specific arrangement of the openings of the glands in various kinds of colonic lesions under magnifying endoscopy[94,95]. Pit patterns basically divided into normal, non-neoplastic (hyperplastic), and neoplastic (adenomatous or cancerous) pattern. Although there are a variety of different classifications the most frequently used is the one described by S. Kudo and colleagues at the Akita Red Cross Hospital, which divides the pit patterns into six groups: types I, II, IIIL, IIIs, IV, and V (Figure 19 and 20). Pit patterns are useful in predicting the histological structure of a lesion. Particularly:

    (1) The pits of the normal mucosa (type I) are round and regular in size and arrangement.

   (2) The pits of non-neoplastic, hyperplastic polyps (type II) are larger than the normal pits, and star-shaped or onion like, but are regularly arranged.

    (3) In polypoid adenomas, the pits often look elongated (type IIIL) The L stands for Long or Large) and sometimes branched (type IV).

    (4) Lesions with compactly arranged pits smaller than the normal ones (type IIIS; the S stands for small or short) are characterized depressed and tend to be early cancers[96,97]. Such lesions are not frequent, but are highlighted nowadays as candidate precursors of advanced cancers of de novo origin. The small pits reflect straight and compactly arranged glands of the lesion. Type IIIL and IIIS pits can be collectively called tubular pits.

    (5) In intramucosal cancer (which might be regarded as high-grade dysplasia in Western countries) the pit pattern is fairly irregular (type V). In invasive cancer reaching the submucosa and in advanced cancer the surface of the lesion is rough and often ulcerated; therefore it is almost devoid of pits. This non-structural pattern devoid of pits is also included in type V.

 

 

 

    The correspondence between type of pit pattern and histological findings is quite well. Particularly, type II pit pattern is corresponding to non-neoplastic lesions in more than 70%, type IIIL, IIIS and IV are corresponding to adenomas in 79.6%, 86% and 75% respectively, type VI is corresponding to carcinoma or high-grade dysplasia in 86% (61% carcinoma and 24% high-grade dysplasia), and VN is corresponding to carcinoma in 93% (65% is corresponding to submucosal invasive cancer).

    The magnifying colonoscope has opened the door to the new field of diagnosing colorectal lesions. It is well established that histopathologic assessment of small lesions by observation with standard endoscopic instruments is imprecise. By magnifying endoscopy, however, it is possible to accurately differentiate true neoplastic tumors from non-tumorous lesions. The routine usage of magnification colonoscopy is assumed to reduce the requirement for biopsies and/or endoscopic resections for the small and numerous surface abnormalities without overt malignant pattern.

    Furthermore, NBI imaging system in colon as in other parts of GI tract reveals specific vascular and mucosal patterns of superficial colonic lesions, which were found effective in distinguishing neoplastic from non-neoplastic lesions, as well as cancers from adenomas, with high accuracy (96.1%) in real time. NBI imaging combined with magnifying endoscopy allows an estimate of the likely histology of a polyp in vivo[26,98]. Wada et al[99], described a standardized NBI magnifying endoscopic classification for colorectal lesions and categorized vascular patterns of colonic neoplastic lesions into six groups (Figure 21).

 

 

    Particularly, the normal colonic mucosa had a honey-comb-like vasculature (Figure 21A), hyperplastic polyp has a faint pattern (Figure 21B) and tubular adenomas showed a regular vessel-network pattern (Figure 21C) on NBI magnification. In villous and tubulovillous adenomas, the vessels were well developed and rather thick, which was the dense pattern (Figure 21D).

    The NBI magnifying vascular structure in high-grade colorectal adenomas and early colorectal cancer varied depending on the different gross appearance of lesions. Protruded high-grade adenomas showed either a vessel-network pattern or a dense pattern (Figures 21 C and D). In protruded submucosally invasive cancers, the vessels were thick and irregular. Definition for irregular vascular pattern according to Wada et al[26] are (a) interruption of the network; (b) a tortuous course of vessels and (c) unusually large caliber of vessels (twice as large as that of surrounding vessels) (Figure 21E). In contrast the depressed-type lesions, especially depressed invasive cancers were characterized with decreased vessels, and this vascular pattern is called a sparse pattern (Figure 21F).

    Based on the six patterns: normal, faint, network, dense, irregular and sparse of the above-mentioned NBI magnifying classification, it is able to differentiate neoplastic from non neoplastic colonic lesions with high sensitivity (83.5%), specificity (98.7%) and accuracy (98.2%), according to Wada et al[9926,98].

 

Follow-up after endoscopic treatment of early GI cancer

Accurate preoperative diagnosis and staging of early GI cancer, based on the technique and classifications described in this article, followed by precise patient selection for endoscopic (EMR or ESD) treatment according to established guidelines, resulted in favorable long-term outcome after curative endoscopic resections also for expanded indications in specialized centers[100-111].

    Particularly, according to recent meta-analysis the local recurrence after ESD for early esophageal cancer was very low (0%-0.3% in mean observation period 19 months) and significantly lower than EMR (9%-11% in mean observation period 30 months)[102,112-115].

   Regarding, early gastric cancer, the annual incidence (2.4%) of metachronous gastric cancer after endoscopic (ESD) resection was constant, with low cumulative 3-year incidence (3.3%-5.9%), while incidence of synchronous gastric cancer was also low (4%)[101,103,105-107]. Metachronous gastric cancers can be also treated curatively with repeat endoscopic resection[116]. ESD for undifferentiated early gastric cancer, is related to higher incidence of synchronous (14.5%) and metachronous (8.5%) gastric cancer, although generally low[108,117].

    In order to detect synchronous or metachronous gastric cancer at an early stage, enough for a curative repeat ESD, an annual endoscopic surveillance program is recommended[101].     

    Finally, local endoscopic resection appears to be also effective for colorectal epithelial neoplasms, (adenomatous polyps and early-stage carcinoma) with overall favorable outcome[100,110,118,119.120]. Furthermore, en bloc colorectal ESD resection resulted in better outcome than piecemeal EMR[100,110,118,119,121]. Colorectal ESD can be also successfully applied as first line salvage therapy in treating residual or locally recurrent neoplastic disease with favorable outcome alternatively to direct surgical resection[122].

 

Conclusions

The evolution in imaging technology (high resolution magnifying endoscopes, combined with chromoendoscopy and enhanced imaging capabilities, such as NBI technology) permitted the incorporation of endoscopic classifications of GI lesions in clinical setting, making precise endoscopic differential diagnosis (mucosal versus submucosal invasion) and staging of superficial GI lesions possible. Subsequently reliable accurate real-time treatment decisions (minimal invasive endoscopic versus surgical treatment) can be made.

    In Japan there are currently in use standardized endoscopic classifications for early GI neoplasia. Pit pattern classification is used for colorectal lesions for years. NBI magnification endoscopy in esophagus, stomach and colorectum enhances both the mucosal microvascular architecture and microsurface structure, revealing specific NBI patterns. The IPCL pattern classification for early esophageal cancer and the NBI magnifying classifications for gastric and colorectal lesions, currently used in Japanese centers, permitted in vivo prediction of histology and are useful tools for reliable, real-time preoperative staging of early GI cancer.

    Local treatment for mucosal GI cancer by endoscopic resection, either endoscopic mucosal rejection (EMR) or endoscopic submucosal dissection (ESD) has been generally accepted as an adequate therapeutic method in Japan, and is growing in the West. In submucosal invasive cancer, however, surgery with complete removal of lymph nodes has been recommended as the standard treatment, because the high incidence of lymph node metastases (approximately 10-40%)[5,26,29,123].

    Finally, in stomach and colorectum, mucosal and slightly invasive submucosal cancer with no lymph node metastasis are good targets for endoscopic local resection (EMR/ESD), while in esophagus upper mucosal cancer only, without lymph node metastases, is indication for endoscopic therapy (EMR/ESD).

 

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

 

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Peer reviewers: Chen Junqiang, Department of Gastrointestinal Surgery, the First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, P.R. China; Gian Luca Baiocchi, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili, III Chirurgia, P.le Spedali Civili, 1, 25123 Brescia, Italy.

 

 

 

 

 

 

 

 

 

 

 

 

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