Kazutomo Togashi

Efficacy of magnifying endoscopy in the differential diagnosis of neoplastic and non-neoplastic polyps of the large bowel

PURPOSE: We have introduced magnifying colonoscopy into clinical practice and analyzed its diagnostic efficacy, especially regarding the ability to distinguish neoplastic from non-neoplastic polyps. METHODS: The materials consisted of 923 polyps. After identifying the lesions during normal colonoscopy, a dye was sprayed, and then the zoom apparatus of the colonoscope was used to make a magnified observation at a maximum 100 times magnification. We classified the crypt orifices into six categories and labeled them A to F as follows: A, a medium round appearance; B, an asteroid appearance; C, an elliptic appearance; D, a small, round appearance; E, a cerebriform appearance; F, no apparent structural appearance. RESULTS: Forty-two of 923 polyps did not reveal any clear images of crypt patterns. The percentage of histologically neoplastic change in the lesions classified as A, B, C, D, E, and F were 10, 15.9, 93.7, 100, 94.8, and 87.5 percent, respectively. When we considered types A and B to represent a crypt pattern of non-neoplastic lesions, and types C, D, E, and F to represent neoplastic lesions, and when the lesions that did not show any clear images were classified as a misjudgment, the diagnostic accuracy of neoplastic lesions (sensitivity) was 92 percent and that of non-neoplastic lesions (specificity) was 73.3 percent. Overall, the diagnostic accuracy in differentiating neoplastic from non-neoplastic lesions was 88.4 percent. Twenty-three neoplastic lesions that were misjudged to be non-neoplastic were histologically adenoma with mild atypia in 22 and adenoma with moderate atypia in 1. CONCLUSION: Magnifying colonoscopy was considered to be useful in determining the indications for colonoscopic removal.

Predictive factors for lymph node metastasis in T1 stage colorectal carcinomas.

PurposeSelective endoscopie resection may cure early colorectal cancer (Tl), but the management is controversial. There is concern about the small risk of lymph node metastasis, which will not be treated by endoscopie resection alone. The authors sought predictive markers of lymph node metastasis to assist patient management. METHODS: The authors retrospectively analyzed consecutive cases of Tl stage colorectal cancer resected using endoscopie resection or bowel surgery over the period 1979 to 2000. The risk of lymph node metastasis was analyzed using logistic regression model for the markers selected by univariate analysis: the type of initial treatment, depth of submucosal invasion, lymphatic channel invasion, differentiation of histology, and invasive front histology. RESULTS: Two hundred seventy-eight patients were available for study. Twenty-one had lymph node metastasis. Depth of submucosal invasion (2 2,000 yum) and lymphatic channel invasion significantly predicted risk of lymph node metastasis in multivariate analysis. When these two factors were adopted for the prediction of lymph node metastasis, sensitivity, specificity, positive predictive value, and negative predictive value were 100, 55.6, 15.6, and 100 percent, respectively. CONCLUSIONS: Depth of submucosal invasion and lymphatic channel invasion were accurate predictive factors for lymph node metastasis. These two factors could be used in selecting appropriate cases for surgery after endoscopie resection.

Evaluation of venous invasion by Elastica van Gieson stain and tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer.

Evaluation of pathologic predictors of metastases in T1 stage colorectal cancer may be difficult with hematoxylin and eosin (HE) staining alone. The aim of this study was to clarify the role of pathologic predictors by using immunohistochemical staining and Elastica van Gieson (EVG) staining. One hundred and twenty-four patients who underwent bowel resection for single T1 stage colorectal cancer from 1990 to 2004 in 1 institution were studied. D2-40, EVG staining, and CAM5.2 were used to detect lymphatic invasion, venous invasion, and tumor budding, respectively. These 3 factors were separately evaluated based on HE staining. Histology was reviewed by 1 pathologist. Lymph node metastases in the surgical specimen were the standard reference, and distant metastases were identified by periodic computed tomography for 2 years or more after surgery. A logistic regression model was applied to analyze risk factors for lymph node metastases and a Cox regression model for distant metastases. In predicting lymph node metastases, univariate analysis demonstrated significance for all predictors except venous invasion by HE staining. Multivariate analysis showed that venous invasion by EVG and tumor budding by HE showed significance as predictors. In predicting distant metastases, univariate analysis showed significance for lymphatic invasion shown by D2-40, tumor budding shown by CAM5.2 and HE, and lymph node metastases. Multivariate analysis showed only venous invasion by EVG stain as being significantly associated with distant metastases (P=0.001). In conclusion, venous invasion evaluated shown by EVG staining is a useful pathologic predictor for metastases in T1 stage colorectal cancer.

Predictive factors for detecting colorectal carcinomas in surveillance colonoscopy after colorectal cancer surgery

PURPOSE: The aim of this study was to identify the high-risk groups for metachronous colorectal carcinoma among patients who undergo colorectal cancer surgery. METHODS: Three hundred forty-one patients undergoing colorectal cancer surgery who had undergone surveillance colonoscopy at least twice during a period of more than three years were analyzed. A metachronous colorectal carcinoma was defined as a new colorectal carcinoma detected by surveillance colonoscopy after surgery. RESULTS: Surveillance colonoscopy was performed 4.6 times per patient during an average of 6.2 years. Twenty-two metachronous colorectal carcinomas in 19 patients were detected, and 14 (64 percent) of 22 were detected within five years of surgery. The cumulative incidence of developing colorectal carcinomas during a five-year period was 5.3 percent. Seventeen (77 percent) of 22 carcinomas were 10 mm or less in size. Ten (71 percent) of the 14 carcinomas in early stages showed a flat appearance. Univariate analysis showed that extracolonic malignancy, coexistence of adenoma, and synchronous multiple colorectal carcinoma were significant predictive factors for detecting colorectal carcinomas in surveillance colonoscopy and that family history of colorectal carcinoma was a possible predictive factor. Multivariate analysis performed with Cox proportional hazards regression model showed that extracolonic malignancy and the coexistence of adenoma were significant predictive factors. CONCLUSION: We recommend that patients with the above predictive factors receive surveillance colonoscopy meticulously and regularly.

Intraoperative localization of colorectal tumors in the early stages using a marking clip detector system

In laparoscopic colectomy the identification of the site of a tumor is often difficult. The topical injection of india ink or blue dye by preoperative colonoscopy is the most prevalent method to mark the tumor site; however, such a procedure also includes the intrinsic danger of possibly injecting dye into the peritoneal cavity. In addition, the injected marker may also spread so widely that the intended site may become obscure. A marking clip detector system was used to detect metallic marking clips in the luminal side that had been applied to the mucosa adjacent to the lesion during the course of preoperative colonoscopy. This method was able to identify the marked site in 40 percent of cases in which only one clip was applied to the mucosa. However, when the lesion sites were marked with two or three clips, then the detection rate increased to 100 percent. Based on our findings, this procedure was found to be a safe and reliable method for identifying lesions during laparoscopic-assisted colectomy.

Microsatellite instability as a marker in predicting metachronous multiple colorectal carcinomas after surgery. A cohort-like study

AbstractPURPOSE: In case-control studies, it was reported that microsatellite instability might be helpful in predicting the development of metachronous multiple colorectal cancers. The purpose of this cohort-like study was to determine whether microsatellite instability is a novel independent marker in predicting metachronous colorectal carcinomas after colorectal cancer surgery. METHODS: Three hundred twenty-eight colorectal carcinoma patients were surveyed by periodic colonoscopy for at least three years after surgery. Among these, DNA from paraffin-embedded sections was available for 272 cases. DNA of these cases was studied for six microsatellite markers (five dinucleotide repeats, one mononucleotide repeat). Microsatellite instability phenotype was defined as alterations in one or more loci. RESULTS: Median follow-up period was 74 months, and the median number of colonoscopies was 4.6. The percentage of microsatellite instability-positive cases was 26.4 percent (72/272). Seventeen metachronous colorectal carcinomas were detected during the follow-up period. Incidences of metachronous colorectal carcinomas in microsatellite instability-positive and microsatellite instability-negative cases were 15.3 and 3 percent, respectively (P < 0.001). The cumulative five-year incidence of metachronous colorectal carcinomas was significantly higher in microsatellite instability-positive cases than in microsatellite instability-negative cases (12.5 vs. 2.5 percent, P < 0.0001). Logistic regression analysis of the relationship between incidence of metachronous colorectal carcinomas and possible risk factors (namely, coexistence of adenoma at the time of surgery, family history of colorectal carcinoma , history of extracolonic malignancy, and microsatellite instability status) showed that microsatellite instability and coexistence of adenoma were significant independent risk factors for the occurrence of metachronous colorectal carcinomas, with values of P = 0.001 and 0.02, respectively. CONCLUSION: These data indicate that microsatellite instability can be regarded as a novel independent and important marker for predicting the development of metachronous colorectal carcinoma after surgery.

Distribution of lymph node metastasis in T1 sigmoid colon carcinoma: should we ligate the inferior mesenteric artery?

Objective In standard oncological sigmoid colectomy, the inferior mesenteric artery is ligated either at its origin or at the level of the left colic artery. However, in patients with early-stage carcinoma, the distribution of metastatic nodes may be limited. The aim of this study was to clarify the prevalence and distribution of lymph node metastasis in T1 sigmoid colon carcinoma and to determine the adequate range of lymph node dissection. Material and methods The study included 121 consecutive patients treated for T1 sigmoid colon carcinoma. Clinicopathologic factors associated with nodal metastasis and the distribution of metastatic nodes were analyzed. Results Conclusions Of 121 patients, 12 (10%) had nodal involvement. The depth of invasion and the presence of lymphatic and vascular invasion were significantly associated with nodal metastasis. Of these 12 patients, 11 (92%) had lymph node metastasis confined to pericolic nodes. Nodes along the sigmoidal artery were involved in one patient. There was no involved node along the superior rectal artery or at the root of the inferior mesenteric artery. Lymph node dissection for T1 sigmoid colon carcinoma should be limited to the root of the sigmoidal artery, and the inferior mesenteric artery should be preserved.

Relationship between the Degree of Endoscopic Atrophy of the Gastric Mucosa and Carcinogenic Risk

Background: The relationship between Helicobacter pylori infection and gastric cancer has been demonstrated, and the risk of gastric cancer occurrence is known to increase with the progression of atrophic changes associated with chronic gastritis. Endoscopic evaluation of the degree and extent of atrophy of the gastric mucosa is a simple and very important means of identifying a group at high risk for gastric cancer. This study aimed to clarify the carcinogenic risk in relation to the degree of atrophy. Methods: A total of 27,777 patients (272 with early gastric cancer and 135 with advanced gastric cancer) were included in this study. Endoscopically evaluated atrophy of the gastric mucosa was classified as C-0 to O-3 according to the Kimura and Takemoto classification system. Results: The cancer detection rate in relation to the degree of gastric mucosal atrophy was 0.04% (2/4,183 patients) for C-0, 0% (0/4,506) for C-1, 0.25% (9/3,660) for C-2, 0.71% (21/2,960) for C-3, 1.32% (75/5,684) for O-1, 3.70% (140/3,780) for O-2 and 5.33% (160/3,004) for O-3. As to the proportions of differentiated and undifferentiated cancers, the latter were relatively frequent in the C-0 to C-2 groups, but differentiated cancers became predominant as atrophy progressed. On the other hand, the number of both differentiated and undifferentiated cancers detected increased as gastric mucosal atrophy progressed. In addition, open-type atrophy was found in 29 (96.7%) of 30 patients with synchronous multiple gastric cancers and in all 20 patients with metachronous multiple gastric cancers. Conclusion: Endoscopic evaluation of gastric mucosal atrophy can provide a simple and reliable predictive index for both current and future carcinogenic risk.

The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes.

Microsatellite instability caused by hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer.

Objective: A subset of sporadic colorectal cancers (SCRCs) exhibits microsatellite instability (MSI). Most MSI in SCRCs is caused by hMLH1 inactivation due to promoter methylation. However, the role of MSI in the progression of SCRCs remains unclear. Methods: Thirty-two intramucosal cancers and 63 cancers with submucosal invasion were assigned to group 1 (early-stage cancer), and 30 Dukes’ B and 26 Dukes’ C cancers to group 2 (advanced-stage cancer). hMLH1 promoter methylation status was determined by methylation-specific PCR. MSI was determined using five markers. hMLH1 expression was determined immunohistochemically. Results: MSI was found in 1 of 95 (1.1%) tumors in group 1, compared with 4 of 56 (7.1%) tumors in group 2. In right-sided tumors, the overall frequency of hMLH1-methylation-positive tumors in group 1 was not significantly different from that in group 2 (17 of 43, 39.5%, vs. 9 of 23, 39.1%). In right-sided tumors with hMLH1 promoter methylation, the frequency of MSI-positive tumors in group 1 was significantly lower than that in group 2 (1 of 17, 5.9%, vs. 4 of 9, 44.4%, p = 0.0081). Conclusion: The frequency of MSI caused by hMLH1 promoter methylation increases with tumor progression in right-sided SCRCs.