Tadakazu Shimoda

The Vienna classification of gastrointestinal epithelial neoplasia

BACKGROUND Use of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions. AIM To develop common worldwide terminology for gastrointestinal epithelial neoplasia. METHODS Thirty one pathologists from 12 countries reviewed 35 gastric, 20 colorectal, and 21 oesophageal biopsy and resection specimens. The extent of diagnostic agreement between those with Western and Japanese viewpoints was assessed by kappa statistics. The pathologists met in Vienna to discuss the results and to develop a new consensus terminology. RESULTS The large differences between the conventional Western and Japanese diagnoses were confirmed (percentage of specimens for which there was agreement and kappa values: 37% and 0.16 for gastric; 45% and 0.27 for colorectal; and 14% and 0.01 for oesophageal lesions). There was much better agreement among pathologists (71% and 0.55 for gastric; 65% and 0.47 for colorectal; and 62% and 0.31 for oesophageal lesions) when the original assessments of the specimens were regrouped into the categories of the proposed Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond). CONCLUSION The differences between Western and Japanese pathologists in the diagnostic classification of gastrointestinal epithelial neoplastic lesions can be resolved largely by adopting the proposed terminology, which is based on cytological and architectural severity and invasion status.

Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers.

Background. The presence of lymph node metastasis (LNM) is the most important prognostic factor for patients with early gastric cancer (EGC). A D2 gastrectomy has been the gold standard treatment. Strict criteria for endoscopic mucosal resection have been widely accepted in Japan. There are some trials aimed at expanding the indications for local treatment, although there has not been a comprehensive review of the risk of LNM with the lesions of EGC. Methods. We investigated 5265 patients who had undergone gastrectomy with lymph node dissection for EGC at the National Cancer Center Hospital and the Cancer Institute Hospital. Nine clinicopathological factors were assessed for their possible association with LNM. Results. None of the 1230 well differentiated intramucosal cancers of less than 30 mm diameter regardless of ulceration findings, were associated with metastases (95% confidence interval [CI], 0–0.3%). None of the 929 lesions without ulceration were associated with nodal metastases (95% CI, 0–0.4%) regardless of tumor size. Similarly to findings for intramucosal cancers, for submucosal lesions, there was a significant correlation between tumor size larger than 30 mm and lymphatic-vascular involvement with an increased risk of LNM. None of the 145 differentiated adenocarcinomas of less than 30-mm-diameter without lymphatic or venous permeation were associated with LNM, provided that the lesion had invaded less than 500 μm into the submucosa (95% CI, 0–2.5%). Conclusion. Based on our large series of cases, we have been able to clarify the risks associated with EGC and to propose expansion of the criteria for local treatment. However, accurate histological evaluation of the resected specimens is essential to avoid recurrence for such EGCs that should be cured.

Endoscopic mucosal resection for treatment of early gastric cancer.

BACKGROUND In Japan, endoscopic mucosal resection (EMR) is accepted as a treatment option for cases of early gastric cancer (EGC) where the probability of lymph node metastasis is low. The results of EMR for EGC at the National Cancer Center Hospital, Tokyo, over a 11 year period are presented. METHODS EMR was applied to patients with early cancers up to 30 mm in diameter that were of a well or moderately histologically differentiated type, and were superficially elevated and/or depressed (types I, IIa, and IIc) but without ulceration or definite signs of submucosal invasion. The resected specimens were carefully examined by serial sections at 2 mm intervals, and if histopathology revealed submucosal invasion and/or vessel involvement or if the resection margin was not clear, surgery was recommended. RESULTS Four hundred and seventy nine cancers in 445 patients were treated by EMR from 1987 to 1998 but submucosal invasion was found on subsequent pathological examination in 74 tumours. Sixty nine percent of intramucosal cancers (278/405) were resected with a clear margin. Of 127 cancers without “complete resection”, 14 underwent an additional operation and nine were treated endoscopically; the remainder had intensive follow up. Local recurrence in the stomach occurred in 17 lesions followed conservatively, in one lesion treated endoscopically, and in five lesions with complete resection. All tumours were diagnosed by follow up endoscopy and subsequently treated by surgery. There were no gastric cancer related deaths during a median follow up period of 38 months (3–120 months). Bleeding and perforation (5%) were two major complications of EMR but there were no treatment related deaths. CONCLUSION In our experience, EMR allows us to perform less invasive treatment without sacrificing the possibility of cure.

Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study.

BackgroundDepth of submucosal invasion (SM depth) in submucosal invasive colorectal carcinoma (SICC) is considered an important predictive factor for lymph node metastasis. However, no nationwide reports have clarified the relationship between SM depth and rate of lymph node metastasis. Our aim was to investigate the correlations between lymph node metastasis and SM depth in SICC.MethodsSM depth was measured for 865 SICCs that were surgically resected at six institutions throughout Japan. For pedunculated SICC, the level 2 line according to Haggitt’s classification was used as baseline and the SM depth was measured from this baseline to the deepest portion in the submucosa. When the deepest portion of invasion was limited to above the baseline, the case was defined as a head invasion. For nonpedunculated SICC, when the muscularis mucosae could be identified, the muscularis mucosae was used as baseline and the vertical distance from this line to the deepest portion of invasion represented SM depth. When the muscularis mucosae could not be identified due to carcinomatous invasion, the superficial aspect of the SICC was used as baseline, and the vertical distance from this line to the deepest portion was determined.ResultsFor pedunculated SICC, rate of lymph node metastasis was 0% in head invasion cases and stalk invasion cases with SM depth <3000 µm if lymphatic invasion was negative. For nonpedunculated SICC, rate of lymph node metastasis was also 0% if SM depth was <1000 µm.ConclusionsThese results clarified rates of lymph node metastasis in SICC according to SM depth, and may contribute to defining therapeutic strategies for SICC.

Early colorectal carcinoma with special reference to its development de novo

The growth type of early colorectal carcinoma was classified into two types. The first type is intramucosal polypoid growth (PG‐Ca) and the second type nonpolypoid growth (NPG‐Ca) which shows mainly massive infiltration of tumor cells below the submucosal layer. The incidence of adenoma‐carcinoma sequence was 72 of 75 lesions (96.0%) in pedunculated polypoid carcinoma, and 61 of 71 lesions (85.9%) in sessile and broad‐based polypoid carcinomas. Their average sizes were 15.0 and 18.7 mm, respectively. Submucosal invasive carcinoma (SM‐Ca) showed a low incidence. They were detected as microscopical or scattered lesions with a few lymphatic and venous permeation. The NPG‐Ca contained 32 lesions. Intramucosal carcinoma without adenoma showing slight depression consisted of ten lesions of which the average size was 5.1 mm. The other 22 lesions showed massive submucosal invasion with marked lymphatic and venous permeation. The average size was 10.3 mm being smaller than PG‐Ca. Histologically, NPG‐Ca was not accompanied with adenoma. The NPG‐Ca arose from de novo carcinoma less than 10 mm in diameter and invaded into the submucosal layer. In advanced carcinoma, the PG‐Ca showed a low incidence (21.8%), and almost all cases were of the NPG type (78.2%). The NPG advanced carcinomas increased in those over the size of 20 mm. It is concluded that nonpolypoid early colorectal carcinomas easily progress to advanced carcinoma, and de novo carcinoma occupied about 80% of colorectal carcinoma.

Differences in diagnostic criteria for gastric carcinoma between Japanese and Western pathologists

BACKGROUND There have been many studies on gastric carcinoma in populations with contrasting cancer risks. We aimed to find out whether the criteria for the histological diagnosis of early gastric carcinoma were comparable in Western countries and Japan. METHODS Eight pathologists from Japan, North America, and Europe individually reviewed 35 microscope slides: 17 gastric biopsy samples and 18 endoscopic mucosal resections taken from 17 Japanese patients with lesions ranging from early gastric cancer to adenoma, dysplasia, and reactive atypia. The pathologists were given a list of pathological criteria and a form on which they were asked to indicate the criteria on which they based each diagnosis. FINDINGS For seven slides most Western pathologists diagnosed low-grade adenoma/dysplasia, whereas the Japanese diagnosed definite carcinoma in four slides, suspected carcinoma in one, and adenoma in only two. Of 12 slides with high-grade adenoma/dysplasia according to most Western pathologists the Japanese gave the diagnosis of definite carcinoma in 11 and suspected in one. Of six slides showing high-grade adenoma/dysplasia with suspected carcinoma according to most Western pathologists the Japanese diagnosed definite carcinoma in all. There were no major differences in the diagnoses of three slides showing reactive epithelium and seven slides with clearly invasive carcinoma. When the opinion of the majority of the pathologists was taken as the final diagnosis there was agreement between Western and japanese in 11 of the 35 slides (kappa coefficient 0.15 [95% CI 0.01-0.29]). Presence of invasion was the most important diagnostic criterion for most Western pathologists whereas for the Japanese nuclear features and glandular structures were more important. INTERPRETATION In Japan, gastric carcinoma is diagnosed on nuclear and structural criteria even when invasion is absent according to the Western viewpoint. This diagnostic practice results in almost no discrepancy between the diagnosis of a superficial biopsy sample and that of the final resection specimen. This may also contribute to the relatively high incidence and good prognosis of gastric carcinoma in Japan when compared with Western countries.

Early Detection of Superficial Squamous Cell Carcinoma in the Head and Neck Region and Esophagus by Narrow Band Imaging: A Multicenter Randomized Controlled Trial

PURPOSE Most of the esophageal squamous cell carcinomas (ESCCs) and cancers of the head and neck (H&N) region are diagnosed at later stages. To achieve better survival, early detection is necessary. We compared the real-time diagnostic yield of superficial cancer in these regions between conventional white light imaging (WLI) and narrow band imaging (NBI) in high-risk patients. PATIENTS AND METHODS In a multicenter, prospective, randomized controlled trial, 320 patients with ESCC were randomly assigned to primary WLI followed by NBI (n = 162) or primary NBI followed by WLI (n = 158) in a back-to-back fashion. The primary aim was to compare the real-time detection rates of superficial cancer in the H&N region and the esophagus between WLI and NBI. The secondary aim was to evaluate the diagnostic accuracy of these techniques. RESULTS NBI detected superficial cancer more frequently than did WLI in both the H&N region and the esophagus (100% v 8%, P < .001; 97% v 55%, P < .001, respectively). The sensitivity of NBI for diagnosis of superficial cancer was 100% and 97.2% in the H&N region and the esophagus, respectively. The accuracy of NBI for diagnosis of superficial cancer was 86.7% and 88.9% in these regions, respectively. The sensitivity and accuracy were significantly higher using NBI than WLI in both regions (P < .001 and P = .02 for the H&N region; P < .001 for both measures for the esophagus, respectively). CONCLUSION NBI could be the standard examination for the early detection of superficial cancer in the H&N region and the esophagus.

Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38–1.89, P = 1.11 × 10−9). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r2 = 0.995, D′ = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56–2.33, P = 8.01 × 10−11). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer

BackgroundEndoscopic resection (ER) has been accepted as minimally invasive treatment in patients with early gastric cancer (EGC) who have a negligible risk of lymph node metastasis. It has already been determined which lesions in differentiated-type EGC present a negligible risk of lymph node metastasis, and ER is being performed for these lesions. In contrast, no consensus has been reached on which lesions in undifferentiated-type (UD-type) EGC present a negligible risk for lymph node metastasis, nor have indications for ER for UD-type EGC been established.MethodsWe investigated 3843 patients who had undergone gastrectomy with lymph node dissection for solitary UD-type EGC at the Cancer Institute Hospital, Tokyo, and the National Cancer Center Hospital, Tokyo. Seven clinicopathological factors were assessed for their possible association with lymph node metastasis.ResultsOf the 3843 patients, 2163 (56.3%) had intramucosal cancers and 1680 (43.7%) had submucosal invasive cancers. Only 105 (4.9%) intramucosal cancers compared with 399 (23.8%) submucosal invasive cancers were associated with lymph node metastases. By multivariate analysis, tumor size 21 mm or more, lymphatic-vascular capillary involvement, and submucosal penetration were independent risk factors for lymph node metastasis (P < 0.001, respectively). None of the 310 intramucosal cancers 20 mm or less in size without lymphatic- vascular capillary involvement and ulcerative findings was associated with lymph node metastases (95% confidence interval, 0–0.96%).ConclusionUD-type intramucosal EGC 20 mm or less in size without lymphatic-vascular capillary involvement and ulcerative findings presents a negligible risk of lymph node metastasis. We propose that in this circumstance ER could be considered.

Efficacy of the Invasive/Non-invasive Pattern by Magnifying Chromoendoscopy to Estimate the Depth of Invasion of Early Colorectal Neoplasms

OBJECTIVE: During colonoscopy, estimation of the depth of invasion in early colorectal lesions is crucial for an adequate therapeutic management and for such task, magnifying chromoendoscopy (MCE) has been proposed as the best in vivo method. However, validation in large-scale studies is lacking. The aim of this prospective study was to clarify the effectiveness of MCE in the diagnosis of the depth of invasion of early colorectal neoplasms in a large series.METHODS: A total of 4,215 neoplastic lesions were evaluated using MCE from October 1998 to September 2005 at the National Cancer Center Hospital, Tokyo, Japan. Lesions were prospectively classified according to the clinical classification of the pit pattern: invasive pattern or non-invasive pattern. All lesions were histopathologically evaluated.RESULTS: There were 3,371 adenomas, 612 intramucosal cancers (m-ca), 232 submucosal cancers (sm-ca): 52 sm superficial (sm1) and 180 sm deep cancers (sm 2–3). Among lesions diagnosed as invasive pattern, 154 out of 178 (86.5%) were sm2–3, while among lesions diagnosed as non-invasive pattern, 4,011 out of 4,037 (99.4%) were adenomas, m-ca, or sm1. Sensitivity, specificity and diagnostic accuracy of the invasive pattern to differentiate m-ca or sm1 (<1000 μm) from sm2–3 (≥1000 μm) were 85.6%, 99.4%, and 98.8%, respectively.CONCLUSION: The determination of invasive or non-invasive pattern by MCE is a highly effective in vivo method to predict the depth of invasion of colorectal neoplasms.