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(BQ) Part 2 book Carly cancer of the gastrointestinal tract endoscopy, pathology, and treatment presents the following contents: Detection of early cancer - Is endoscopic ultrasonography effective; endoscopic treatment; natural course of early cancer; surgical treatment and survival rate of early cancer.
III Early Neoplasia in Barrett’s Esophagus Early Neoplasia in Barrett’s Esophagus Manfred Stolte, Michael Vieth, Andrea May, Liebwin Gossner, Irina Dostler, and Christian Ell Introduction Over the last 10–20 years, the incidence of adenocarcinomas in Barrett’s esophagus has increased enormously in many Western countries [1–5] The increase in these countries is greater than that of all other malignant epithelial tumors, so that the term “new epidemic” has even been applied [6] The aim of gastroenterologists and pathologists must therefore be to diagnose this neoplasia at as early a stage as possible and thus enable curative endoscopic therapy A review of the older literature up to the middle of the 1990s leaves the impression that we are far from achieving this objective, since these older publications report mostly advanced Barrett’s adenocarcinomas, with the 5-year survival rate varying between 7% and 20% [7] Over the last years, however, as a result of great advances in diagnostic endoscopy there has been a positive change Ever more frequently, early-stage neoplasia is being detected endoscopically, diagnosed in biopsy material, and treated via the endoscope [8–11] Ten years ago, we at the Institute of Pathology of the Bayreuth Hospital diagnosed advanced Barrett’s carcinomas almost exclusively The above-mentioned progress in diagnostic endoscopy has resulted in an increase in the percentage of early neoplasias we have diagnosed over the last years to 50%–60% With regard to the endoscopic diagnosis of early Barrett’s carcinomas, we were initially of the opinion that the macroscopic classification of early gastric carcinoma could also be applied to Barrett’s esophagus Our initial evaluation of the macroscopic types of early Barrett’s carcinoma in analogy to early gastric carcinoma in 200 endoscopic mucosectomy specimens, however, then showed that the early carcinomas in Barrett’s esophagus often present no uniform macroscopic appearance, but, rather, show a mixed pattern (see Table 1) This is due in particular to the fact that the early carcinoma often does not grow focally, but in a circular fashion over a larger area (see Fig 1) On the basis of the macroscopic and histological findings, the following endoscopic presentations can be conTable Macroscopic classification of early Barrett’s carcinomas in 200 patients, in analogy to the classification of early gastric carcinomas Barrett’s neoplasia Type I Type IIa Type IIb Type IIc Type III 11.5% 28.3% 17.7% 3.8% 1.7% Mixed type 37.0% How Histology Helps to Improve the Endoscopic Diagnosis of Early Neoplasia in Barrett’s Esophagus Formerly it was believed that “dysplasia” of Barrett’s mucosa could be diagnosed only histologically, and therefore quadrant biopsies at intervals of 1–2 cm were recommended [12, 13] “Dysplasia,” however, is defined as unequivocal intraepithelial neoplasia [14] We therefore earlier postulated that, where something “new” is growing, the surface structure of the mucosa must also be altered, and were of the opinion that, with special endoscopic techniques such as chromoendoscopy and magnification videoendoscopy, such neoplasia could be recognized and submitted to targeted biopsy [15] Fig Operative specimen with a circular growing early mucosal Barrett’s adenocarcinoma with irregular surface 143 144 III Early Neoplasia in Barrett’s Esophagus Fig Normal vascularization of Barrett’s mucosa without neoplasia (immunohistochemical marking of the endothelial cells of the capillaries with CD 34 antibody) Fig Increased vascularization of Barrett’s mucosa with high-grade intraepithelial neoplasia (immunohistochemistry with CD 34 antibody) Figs and Focal adenocarcinoma in a short Barrett’s esophagus prior and after methylene blue staining sidered suspicious for neoplasia and are detectable with the various endoscopic techniques indicated: As a result of the “new growth,” the following changes in the surface structure of Barrett’s mucosa may occur: —irregular verrucous or papillary areas, and —elevations or broad-based polyps Such alterations must therefore be detectable with high-resolution video-endoscopy and magnification videoendoscopy Invasive neoplasia is also characterized by infiltrative and destructive growth Erosions and ulcers in Barrett’s mucosa must be considered as suspicious findings that require targeted biopsy Neoplasia also leads to the replacement of the goblet cells, which can be visualized with negative methylene blue chromoendoscopy Neoplasia in Barrett’s esophagus induces an increase in angiogenesis (see Figs and 3), so that during videoendoscopy, a search should also be for foci of increased redness in the salmon-colored Barrett’s mucosa Early carcinomas in Barrett’s mucosa reveal considerable disruption of the architecture of the neoplastic tubules (irregular budding and branching) This Early Neoplasia in Barrett’s Esophagus 145 Figs and High-grade intraepithelial neoplasia in the short Barrett’s esophagus: overview and after magnification endoscopy in combination with acetic acid 1.5% A B Fig 8A,B Early Barrett’s adenocarcinoma type IIa after magnification endoscopy with acetic acid 1.5% histological finding may in future be a “diagnostic search criterion” for new imaging methods such as optical coherence tomography [16, 17] and intravital endoscopic microscopy [18, 19] In addition, early carcinomas are characterized by invasive growth The best means of detecting this invasive growth and its extent (depth of infiltration) is endosonography carried out with 20 MHz miniprobes [20] Endoscopic Findings in Early Neoplasia in Barrett’s Mucosa According to the above-described morphological patterns discrete changes in color, structure, and mucosal architecture within the Barrett’s segment have to be visualized during endoscopy Small nodules, increased redness, or irregular cobblestone-like pattern are typical for neoplasia in Barrett’s A distorted mucosal pattern 146 III Early Neoplasia in Barrett’s Esophagus or small erosive alterations of the mucosa are also signs for malignant degeneration High-resolution endoscopy in combination with vital stains such as methylene blue and acetic acid help to delineate such lesions (Figs 4–8) Histology of Early Neoplasia Barrett’s adenocarcinoma arises from intraepithelial neoplasia (dysplasia) which is classified as low grade or high grade In this stage, the neoplasia cannot metastasize, but early Barrett’s adenocarcinomas limited to the mucosa also very rarely metastasize The aim of diagnostic endoscopy/biopsy, therefore, must be the histological detection of neoplasia in these early stages Histological diagnosis of these early neoplasia is, however, still very uncertain, and interobserver variation relatively poor [21–25] This is also confirmed by the evaluation of our consultational diagnostic work done in 2001 [26]: regenerative changes are frequently overdiagnosed as low-grade dysplasia, and carcinomas are not infrequently underdiagnosed as high-grade dysplasia (see Table 2) Furthermore, the extremely variable reported prevalence of low-grade dysplasia in numerous publications (see Table 3) indicates that regenerative changes in Barrett’s mucosa are obviously overdiagnosed as lowgrade dysplasia the world over [27–33] Table Comparison of Barrett’s neoplasia diagnoses submitted for a second opinion with the corrected diagnoses [26] Barrett LGIEN HGIEN Ca LGIEN (n = 89) 75.0% 7.5% 5.0% 12.5% HGIEN (n = 122) 29.5% 0.8% 13.1% 56.6% Ca (n = 67) 13.4% — — 86.6% Differential Diagnosis Between Regenerative Changes and Low-Grade Dysplasia in Barrett’s Mucosa This differential diagnosis is apparently the most uncertain borderline area in the histological diagnostic workup of Barrett’s mucosa In many cases, back-toback glands located at the base of Barrett’s mucosa with hyperchromatic nuclei and increased mitotic figures are overdiagnosed as low-grade dysplasia (Fig 9) Back-toback glands, however, are merely a result of the pdivision during the regenerative process [34] The nuclei in the basal third of the regenerative glands have compact chromatin without prominent nucleoli, the epithelium matures steplessly in the apical direction, and the surface epithelium is normal [35–37] In low-grade intraepithelial neoplasia (dysplasia) the architecture of Barrett’s mucosa with parallel arrangement of glands is largely normal The neoplastic epithelial cells with basally located, often peg-like nuclei extend up to the surface epithelium of Barrett’s mucosa and reveal an abrupt transition to the neighboring Barrett’s epithelium (Fig 10) Unfortunately, we have no reliable immunohistochemical or molecular-pathological markers for the differentiation of the regenerative changes from lowgrade intraepithelial neoplasia In the individual case, immunohistochemical examinations with an antibody against Ki67 or p53 may be useful [38–40] On the basis of our experience, we would draw attention to the fact that the reliable biopsy-based diagnosis of low-grade intraepithelial neoplasia may merely be the tip of the iceberg, so that low-grade intraepithelial neoplasia may also be an extension of a high-grade intraepithelial neoplasia or an adenocarcinoma LGIEN, low-grade intraepithelial neoplasia; HGIEN, high-grade intraepithelial neoplasia; Ca, Barrett’s adenocarcinoma Table Differences in the incidence of the diagnosis of a lowgrade intraepithelial neoplasia (LGIEN) in published studies First author [Ref.] Year LGIEN Schnell [27] Sharma [28] Egger [29] O’Connor [30] Fisher [31] Gopal [32] Conio [33] Own material 2002 2003 2003 1999 2003 2003 2003 2003 67.2% 25.0% 20.2% 17.6% 13.5% 9.7% 9.6% 2.2% Fig Regenerative changes in Barrett’s mucosa, often overdiagnosed as “low-grade dysplasia” Early Neoplasia in Barrett’s Esophagus Differential Diagnosis Between Low-Grade and High-Grade Intraepithelial Neoplasia of Barrett’s Mucosa In the case of high-grade intraepithelial neoplasia, too, the normal architecture of Barrett’s mucosa is relatively well preserved As in low-grade intraepithelial neoplasia, the epithelium of Barrett’s glands has been replaced by neoplastic epithelium In comparison with the epithelium of low-grade intraepithelial neoplasia, however, neoplastic epithelium in high-grade dysplasia reveals all the cytological criteria of malignancy The Fig 10 Low-grade intraepithelial neoplasia (“dysplasia”) with extension up to the surface of Barrett’s mucosa and abrupt transition to the neighboring epithelium 147 nuclei show an irregular arrangement (loss of polarity, more marked polymorphism and hyperchromatism with irregularly structured chromatin, with prominent nucleoli and increased pathological mitotic figures [Figs 11 and 12]) Differential Diagnosis Between High-Grade Intraepithelial Neoplasia and Adenocarcinoma in Barrett’s Mucosa As in the case of high-grade intraepithelial neoplasia, all the above-mentioned cytological criteria of malignancy are also found in well-differentiated Barrett’s adenocarcinoma In addition, invasive growth of the neoplastic tubuli is to be seen This architectural disruption is interpreted by many American pathologists to be a “partial substrate” of high-grade intraepithelial neoplasia, and not invasive intramucosal carcinoma [41–43] These pathologists diagnose carcinoma only when there is disruption of the neoplastic glands with single tumor cells within the lamina propria and solid invasive trabecular tumor pegs are found In our own experience, however, these criteria are to be seen only in moderately or poorly differentiated adenocarcinomas, but not in well-differentiated adenocarcinoma We are of the opinion that—in analogy to well-differentiated early gastric carcinoma [44–46]— transversally arranged interconnected neoplastic tubuli must be interpreted as invasive growth through the lamina propria Militating in favor of this interpretation is the fact that these well-differentiated tubular Barrett’s adenocarcinomas often fail to show any tumor Figs 11 and 12 High-grade intraepithelial neoplasia of Barrett’s mucosa 148 III Early Neoplasia in Barrett’s Esophagus cell dissociation, even in the invasive front in the newly formed muscularis mucosae, the original lamina propria of the esophageal mucosa, the original muscularis mucosae, and the submucosa, but are here characterized by invasive neoplastic tubuli (Figs 13 and 14) When confronted by such findings in the endoscopic mucosectomy specimens or surgical specimens, most Western pathologists also diagnose adenocarcinoma—as in the case of well-differentiated tubular adenocarcinoma in the stomach or colorectum This is also shown by a comparison of the diagnosis of high-grade intraepithelial neoplasia in biopsy material with the definitive diagnosis in the surgical specimen: in 40%–70% of the cases [47, 48], a carcinoma is diagnosed in the surgical specimen, in some cases with evidence of advanced carci- noma [49, 50] This is not at all surprising, since our experience shows that well-differentiated Barrett’s carcinomas often mimic high-grade intraepithelial neoplasia at the surface, while invasive carcinoma is unequivocally diagnosed in the base (Figs 15 and 16) For this “borderline area,” again, no immunohistochemical or molecular-pathological markers are available for the differential diagnosis between highgrade intraepithelial neoplasia and well-differentiated Barrett’s adenocarcinoma In such a case, the “eye of the pathologist” remains the gold standard [51] Basically, however, this differential diagnosis is merely “academic,” since the consequences to be drawn from a diagnosis of high-grade intraepithelial neoplasia in biopsy material should always be endoscopic treatment Fig 13 Barrett’s adenocarcinoma with invasion of the muscularis mucosae Fig 14 Barrett’s adenocarcinoma with invasion of the superficial submucosal layer Figs 15 and 16 Barrett’s adenocarcinoma with the appearance of high-grade intraepithelial neoplasia in the upper part of the mucosa Early Neoplasia in Barrett’s Esophagus Table Frequency of the histological diagnoses in 1011 endoscopic resection preparations from 399 patients No neoplasia LGIEN HGIEN pT1-m-Ca pT1-sm1-Ca pT1-sm2-Ca pT1-sm3-Ca 2.0% 1.2% 3.2% 79.7% 6.3% 3.8% 3.8% n = 399; 1011 endoscopic resections The fact that the indication for endoscopic resection based on a special gastroenterological diagnostic workup is correct in approximately 90% of the cases is confirmed by our evaluation of endoscopic resection specimens obtained from 399 patients (see Table 4): most neoplasias removed by endoscopic resection were limited to the mucosa, and surgical treatment was necessary in only a few patients in whom the histological workup revealed invasion of the submucosa 149 Table Incidence of lymph node metastases (N+) in surgical specimens with Barrett’s adenocarcinomas confined to the mucosa (pT1m), and in Barrett’s carcinomas infiltrating into the submucosa (pT1sm) pT1m pT1sm First author [Ref.] Year n N+ n N+ Rice [52] Hölscher [53] Ruol [54] van Sandvick [55] Stein [56] Dar [41] Westerterp [57] 1997 1997 1997 2000 2000 2003 2005 29 10 12 38 20 54 3% 0% 0% 0% 0% 0% 2% 17 31 22 20 56 66 8% 10% 36% 30% 18% 0% 56% Is Endoscopic Resection Adequate Treatment for Early Neoplasia of Barrett’s Mucosa? The justification for the limited endoscopic treatment is provided by six publications on the incidence of regional lymph node metastases in esophagectomy specimens [41, 52–57] In the case of early carcinomas limited to the mucosa, only two of the seven publications reported finding lymph node metastases, in 2–3% of the cases, while infiltration of the submucosa was associated with an increase in lymph node metastases to between 8% and 56% (see Table 5) In none of these studies was the depth of infiltration in the mucosa and submucosa further differentiated in more detail In analogy to the classification of early squamous cell carcinoma [58], we initially differentiate the depth of infiltration of Barrett’s adenocarcinomas as follows: m1 = carcinoma limited to Barrett’s mucosa m2 = carcinoma infiltrating the newly formed muscularis mucosae of Barrett’s mucosa m3 = carcinoma infiltrating the original lamina propria of the esophageal mucosa m4 = infiltration of the original muscularis mucosae of the esophageal mucosa sm1 = infiltration of the superficial third of the submucosa sm2 = infiltration of the middle third of the submucosa sm3 = infiltration of the deep third of the submucosa Whether this differentiated classification of the depth of infiltration is of any practical value, e.g., whether m4 Fig 17 Poorly differentiated Barrett’s mucosa microadenocarcinoma in carcinomas more frequently metastasize to the lymph nodes than m1 carcinoma, or whether, e.g., in analogy to early gastric carcinoma, sm1 carcinomas relatively rarely metastasize to the lymph nodes, may be answered by the results of our currently ongoing follow-up investigations As a working hypothesis: in the absence of such data, the risk of metastasis can, for the present, in analogy to early gastric carcinoma, be differentiated as follows: Low risk —Depth of infiltration limited to the mucosa (m1 to m4) —Well to moderately well-differentiated adenocarcinoma (G1, G2) —No invasion of lymphatic or blood vessels (L0, V0) High risk —Depth of infiltration—into the submucosa (sm1 to sm3), or —Poorly differentiated (Fig 17) and undifferentiated carcinoma (G3, G4), or 150 III Early Neoplasia in Barrett’s Esophagus 10 Different Endoscopic Resection Techniques Fig 18 Barrett’s adenocarcinoma with invasion of a lymphatic vessel The endoscopic resection (ER) techniques used depend on the anatomical conditions, the macroscopic type of the early carcinoma, and the endoscopist’s personal experience However, ER of intraepithelial neoplasias or early carcinomas in Barrett’s esophagus is difficult, as most of the lesions are superficial and lie in an axial hiatal hernia in the area of the esophagogastric junction In our view, there are two techniques that are particularly appropriate in the esophagus: in protruded lesions, removal after injection under the lesion using the polypectomy technique, with loops adapted to the size of the lesion; in superficial lesions, the “suck-and-cut” technique with a ligation device or cap, which has proven its value 10.1 Strip Biopsy —Invasion of lymphatic or blood vessels (L1, V1) (Fig 18) Further follow-up investigations will be required to show whether this risk classification is correct Results of Surgical Treatment of Early Neoplasia of Barrett’s Mucosa Radical esophageal resection has until now been the standard treatment for patients with early neoplasia in Barrett’s esophagus However, it is associated with high rates of mortality and morbidity Even in specialized centers with highly selected patient populations, the mortality in patients with neoplasias is more than 3%, while morbidity rates of 20%–50% are reported [3, 59] In patients over the age of 70, the mortality increases to as much as 11% [60] Another aspect that needs to be taken into account is that patients require at least months postoperatively to achieve a quality of life similar to that which they had before the operation [61] A further argument in favor of local therapy is the virtually nonexistent risk of lymph node metastases in intraepithelial neoplasias and mucosal early carcinomas [41, 52–57] It is only when infiltration of the submucosa takes place that lymph node metastases are encountered, in 8%–56% of cases [52–57, 62] Exact pretreatment staging using chromoendoscopy, miniprobe endosonography, and computed tomography is therefore indispensable [63] In strip biopsy, a diathermy loop is introduced through the working channel of the endoscope and positioned over a protruded lesion, which is fixed by tightening of the loop and slowly detached using an electrical cutting current This technique can be used in (type I) protruded tumors, but with superficial lesions it is difficult to position the loop, and there may be a risk that the size of the removed specimen will be limited Nevertheless, this technique has been advocated and has been successfully used in the resection of five superficial early Barrett’s carcinomas [64] Submucosal injection of a solution can lift superficial elevated, flat or shallow depressed lesions (type II) and make it easier to resect them (the “lift-and-cut” technique) In addition to extending the range of target lesions in comparison with simple strip biopsy,this procedure also has other advantages Injection of a saline– epinephrine solution into the submucosa, for example, lifts the early carcinoma—thereby increasing the distance from the muscularis propria and potentially reducing the risk of perforation A second advantage of the injection technique may be a reduced risk of hemorrhage, due to the vasoconstriction caused by epinephrine and compression by the injected volume of liquid The type of injection solution used has not been standardized The solution most often used is saline with epinephrine or dextrose in various concentrations We use 10 ml of a : 100 000 epinephrine–saline solution A disadvantage of the epinephrine–saline mixture is its short retention time (3.0 min) in comparison with a 50% dextrose solution (4.7 min) and a 1% rooster-comb hyaluronic acid solution (22.1 min) These data were Early Neoplasia in Barrett’s Esophagus obtained in an animal-experiment study in the porcine esophagus [65] 10.2 “Suck-and-Cut” Technique The “suck-and-cut” technique is used in the esophagus more frequently than strip biopsy, due to the anatomical conditions, and our group also uses it almost exclusively The rationale is that a study by Tanabe et al [66] demonstrated that endoscopic suck-and-cut mucosectomy in early gastric cancer is more effective than strip biopsy with regard to the largest diameter of the resected specimen, the rate of en bloc resection, and the complication rate In the early 1990s, Inoue and Endo developed the cap technique, thereby improving the effectiveness of ER in comparison with simple strip biopsy [67] In the ER cap technique, a specially developed transparent plastic cap is attached to the end of the endoscope After injection under the target lesion, the lesion is sucked into the cap and resected with a diathermy loop that has previously been loaded into a specially designed groove on the lower edge of the cap Since injecting underneath early carcinomas often makes it difficult to distinguish them, prior marking of the lesion, e.g., using electrocautery, is recommended (Fig 19a–e) Another resection technique of the “suck and cut” principle is the ligation technique In this method, the target lesion is sucked into the ligation cylinder, and a polyp is created by releasing a rubber band around it The polyp is then resected at its base, either above or below the rubber band, using a diathermy loop (Fig 20a–d) In this technique, the endoscope being used for resection has to be withdrawn again and reintroduced in order to remove the ligation cylinder and introduce the loop Ligation devices available include, in addition to single-use devices, a reusable ligator [68], with which similar results can be achieved at reduced cost A study conducted by our research group compared the two suction mucosectomy techniques—the cap technique and the ligation technique—in the resection of early esophageal neoplasias [69] In this prospective study, 100 consecutive endoscopic mucosal resections were performed in 70 patients with early esophageal cancer Fifty resections were carried out with the ligation device without prior injection, and 50 resections using the cap technique with prior submucosal injection with a diluted epinephrine–saline solution The main criteria were the maximum diameter of the resected specimen, the resection area, and the complication rate No significant differences were observed between the two groups with regard to the maximum diameter of the resected specimens and the resection area after 24 h 151 There was only a slight advantage for the ligation group in patients who had had prior treatment One minor bleeding incident occurred in each group, but no severe complications were seen In addition to the suck-and-cut and strip biopsy techniques, ER using a double-channel endoscope has also been described [70] In this method, a grasping forceps is used to pull the target lesion through a diathermy loop that has been introduced through the second working channel The lesion is then resected with the loop Due to the large caliber of the endoscope required, double-channel procedures appear to be very difficult, especially at the esophagogastric junction, and may even be almost impossible in the inverted position in short-segment Barrett’s neoplasia The latest technique is the “en bloc” ER by using “endoknives” as for early gastric cancer However, for this technique experience in Barrett’s esophagus is limited 11 Endoscopic Resection of Early Neoplasia in Barrett’s Esophagus Our research group has now conducted more than 1500 ERs in the esophagus in a total of more than 650 patients who presented to our institution with early Barrett’s carcinoma or high-grade intraepithelial neoplasia (HGIN) between October 1996 and June 2005, and who underwent endoscopic treatment with curative intent The first major interim report from a prospective series of 64 patients with early Barrett’s carcinoma or high-grade intraepithelial neoplasia was published by our group in 2000 [8] Complete remission was achieved in 82.5% of cases (97% in the low-risk group, 59% in the high-risk group) During a mean follow-up period of 12 months, recurrences or metachronous carcinomas were observed in 14% of the patients, and these again underwent successful endoscopic treatment The rate of serious and mild complications in this study was 12.5% More recent publications by our group have also confirmed the effectiveness of ER in 50 patients with early neoplasias in short-segment Barrett’s esophagus [71] Twenty-eight patients received ER, 13 underwent photodynamic therapy (PDT), and three were treated with argon plasma coagulation (APC) A combination of these therapies was used in six patients Complete local remission was achieved in 98% of the patients; one patient was switched to surgery after initial ER treatment, as there was submucosal tumor infiltration In this study, the minor complication rate was again very low, at 6% (bleeding, stenosis), and no major complications were observed Surgical Treatment and Survival Rate of Early Cancer 261 Table Correlation between lymph node involvement, tumor size, and histological type in submucosal cancer Size (cm) Differentiated type Undifferentiated type n0 n1 n2 n3 and/or n4 n0 n1 n2 n3 and/or n4 £0.5 0.6–1.0 1.1–2.0 2.1–3.0 3.1–4.0 4.1–5.0 ≥5.1 (100.0) 35 (97.2) 98 (88.3) 93 (80.9) 134 (79.3) 112 (70.4) 48 (64.0) (0) (2.8) 12 (10.8) 14 (12.2) 25 (14.8) 34 (21.4) 18 (24.0) (0) (0) (0.9) (7.0) 10 (5.9) 13 (8.2) (12.0) 0/8 (0) 0/36 (0) 1/111 (0.9) 8/115 (7.0) 10/169 (5.9) 13/159 (8.2) 9/75 (12.0) (100.0) 25 (78.1) 78 (89.7) 102 (80.3) 145 (81.9) 106 (70.2) 62 (70.5) (0) (18.8) (9.2) 20 (15.8) 25 (14.1) 32 (21.2) 16 (18.2) (0) (3.1) (1.2) (3.9) (4.0) 13 (8.6) 10 (11.3) 0/6 (0) 1/32 (3.1) 1/87 (1.1) 5/127 (3.9) 7/177 (5.5) 13/151 (8.6) 10/88 (11.4) Total 528 (78.5) 104 (15.5) 38 (5.6) 38/673 (5.6) 524 (78.4) 107 (16.0) 37 (5.6) 37/668 (5.5) Source: Department of Surgery, Cancer Institute Hospital, 1952–1999 Percentages are given in parentheses Table Cumulative 5-year survival rate of patients with standard D2 surgery Stage IA IB II IIIA IIIB IV Total +E U M L Whole Total 71.4 (7) 68.8 (21) 44.9 (28) 33.7 (30) 21.7 (24) 16.1 (40) 88.0 (225) 82.5 (163) 63.7 (117) 44.6 (137) 26.2 (73) 17.1 (120) 95.1 (910) 91.0 (300) 72.7 (200) 57.0 (150) 35.4 (71) 23.2 (92) 93.0 (854) 86.6 (243) 66.1 (198) 53.0 (167) 35.2 (98) 13.6 (152) 100.0 (8) 57.1 (7) 66.6 (19) 17.0 (25) 10.1 (28) 11.0 (67) 93.4 (2030) 87.0 (725) 68.3 (541) 50.1 (485) 30.8 (273) 16.6 (440) 35.9 (150) 61.3 (835) 82.6 (1723) 74.8 (1712) 25.6 (154) 73.7 (4494) Source: Japanese Gastric Cancer Association, registered cases in 1991 Percentages are given in parentheses +E, positive for esophageal invasion; Whole, whole stomach; U, M, L, upper, middle, and lower third of the stomach dissection of the Group and no lymph nodes (at the root of the left gastric artery), limited resection of the stomach, and omission of burso-omentectomy In mucosal cancer, the site of lymph node metastasis in the N2 group was the no lymph node, if present, and peritoneal recurrence was quite rare [15, 16], leading to limited lymph node dissection and preservation of the greater omentum for curative treatment From 1980 to 1993, we performed limited surgery on 188 patients with early cancer preoperatively diagnosed with mucosal cancer and Stage Ia The depth of cancer invasion was evaluated by a barium meal examination, endoscopy, and endoscopic ultrasonography (EUS) Intraoperatively, the stage of cancer was confirmed as Stage Ia and the lesion was palpated from the serosal side When it was palpable, the patient was excluded from limited surgery and underwent D2 lymphadenectomy Cancer invading the deep submucosal layer or the muscle layer is easily palpable Furthermore, as men- Table Macroscopic type and depth of cancer invasion in our series of limited surgery Macroscopic type Depth m sm Elevated (n = 38) Depressed (n = 142) Combined (n = 8) 31 (81.6%) 110 (77.5%) (37.5%) (18.4%) 32 (22.2%) (62.5%) Total 144 44 Table Data of patients with lymph node involvement in our series of limited surgery Depth m sm 5/144 (3.5%) 5/44 (11.4%) LN group 10 Macroscopic type Elevated Depressed Combined 10 Ulceration (+) (-) Histological type Intestinal Diffuse Tumor size (cm) 3.8 ± 2.6a LN, lymph node a Mean ± SD tioned above, peptic ulceration within the lesion predisposes to cancer invasion and lymph node involvement Fibrous tissue due to ulcer formation is frequently palpated as an induration Accordingly, palpation of the lesion is a simple and effective method for the diagnosis of not only cancer invasion, but also the presence of an ulcer or ulcer scar The results of limited surgery are shown in Tables and There was cancer invasion to the mucosal and submucosal layers in 144 patients (76.6%) and 44 patients (23.4%), respectively, and there was no case of advanced cancer Cancer invasion was correctly diag- 262 VII Surgical Treatment and Survival Rate of Early Cancer nosed in approximately 80% of the elevated and of the depressed types Since the adoption of EUS in 1987, only two cases have been misdiagnosed in terms of depth of cancer invasion in the elevated type However, in the combined type, more than half of the cases were submucosal cancer and the preoperative diagnosis of cancer invasion was unsatisfactory (Table 7) Clinically, it is well known that this type of cancer mimics type cancer and frequently invades the lymphatic and vascular systems, even when it is small After this experience, the combined type was fundamentally excluded from limited surgery In our series of limited surgery, lymph node involvement was observed in 10 patients (5.3%); were mucosal and were submucosal cancers They were all of the depressed type and of them (90%) were accompanied by an ulcer or ulcer scar within the lesion The mean size of the lesion was 3.8 cm in diameter Only one lesion was without ulceration and measured cm in diameter (Table 8) Therefore, one should be cautious of performing limited surgery if a lesion is large or is accompanied by an ulcer or ulcer scar In comparison with standard radical surgery, limited surgery resulted in a significantly shorter operating time, less blood loss, and lower incidence of blood transfusion (Table 9) Conclusively, we have had no cases of cancer recurrence after limited surgery 1.5 Japanese Guidelines for the Treatment of Early Gastric Cancer The Japanese Gastric Cancer Association proposed clinical guidelines for the treatment of early gastric NO T1 (M) IA EMR (en bloc resection) (differentiated type, ≤2.0 cm, without ulceration) cancer in 2001, mainly based on obvious evidence and numerous clinical results, including those of limited surgery Strategies for the treatment of early gastric cancer are postulated in detail according to the status of cancer invasion and lymph node involvement as follows: endoscopic mucosal resection (EMR) for cancers limited to the mucosa, pathologically intestinal type, measuring less than cm in diameter and showing no ulceration; limited surgery A (gastrectomy with D1 + no.7 lymph node dissection, and additionally no 8a lymph node dissection if the tumor is located in the antrum) for other mucosal cancers and for those with pathologically intestinal type invading the submucosa and measuring less than 1.5 cm in diameter; limited surgery B (gastrectomy with D1 + no 7, 8a, lymph node dissection) for cancers limited to the mucosa, macroscopically N1-positive but N2-negative, and measuring less than cm in diameter, or for those not adaptable to limited surgery A and invading the submucosa but macroscopically node negative Cases of early gastric cancer not fulfilling the above-mentioned criteria should undergo standard radical surgery with D2 lymph node dissection (Fig 1) Table Operating time, blood loss, and blood transfusion in limited surgery compared with standard surgery Operating time (h) Blood loss (g) Incidence of transfusion Limited surgery Conventional surgery P value 3.8 ± 1.0 311 ± 194 6/188 (3.2%) 4.6 ± 1.0 502 ± 485 14/136 (10.3%)