Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp Study.

BACKGROUND & AIMS: To date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. METHODS: This was a prospective cohort study of participants from the Japan Polyp Study conducted at 11 Japanese institutions. Participants underwent scheduled follow-up colonoscopies after a 2-round baseline colonoscopy process. The primary outcome was CRC incidence after randomization. The observed/expected ratio of CRC was calculated using data from the population-based Osaka Cancer Registry. Secondary outcomes were the incidence and characteristics of advanced neoplasia (AN). RESULTS: A total of 1895 participants were analyzed. The mean number of follow-up colonoscopies and the median follow-up period were 2.8 years (range, 1-15 y) and 6.1 years (range, 0.8-11.9 y; 11,559.5 person-years), respectively. Overall, 4 patients (all males) developed CRCs during the study period. The observed/expected ratios for CRC in all participants, males, and females, were as follows: 0.14 (86% reduction), 0.18, and 0, respectively, and 77 ANs were detected in 71 patients (6.1 per 1000 person-years). Of the 77 ANs detected, 31 lesions (40.3%) were laterally spreading tumors, nongranular type. Nonpolypoid colorectal neoplasms (NP-CRNs), including flat (<10 mm), depressed, and laterally spreading, accounted for 59.7% of all detected ANs. Furthermore, 2 of the 4 CRCs corresponded to T1 NP-CRNs. CONCLUSIONS: Endoscopic removal of premalignant lesions, including NP-CRNs, effectively reduced CRC risk. More than half of metachronous ANs removed by surveillance colonoscopy were NP-CRNs. The Japan Polyp Study: University Hospital Medical Information Network Clinical Trial Registry: University Hospital Medical Information Network Clinical Trial Registry, C000000058; cohort study: UMIN000040731.

Association between continuous cessation or reduction of drinking alcohol and improvement of multiple dysplastic lesions in patients with esophageal squamous cell carcinoma after endoscopic resection.

BACKGROUND: Multiple development of squamous cell carcinoma (SCC) in the upper aerodigestive tract has been explained by the 'field cancerization phenomenon' associated with alcohol drinking. Squamous dysplastic lesion is clinically visualised as a Lugol-voiding lesion (LVL) by chromoendoscopy. Whether cessation or reduction of alcohol drinking improves multiple LVL and reduces the risk of field cancerization has not been elucidated. METHODS: We analysed 330 patients with newly diagnosed superficial esophageal SCC (ESCC) enrolled in the cohort study. The grade of LVL was assessed in all patients every 6 months. We instructed the patients to stop smoking and drinking and recorded their drinking and smoking status every 6 months. RESULTS: Among 330 patients, we excluded 98 with no LVL or no drinking habit. Of the remaining 232 patients, 158 continuously ceased or reduced their drinking habit. Patients who ceased or reduced their drinking habit significantly showed improvement in the grade of LVL. Multivariate analysis showed that continuous cessation or reduction of drinking habit improved the grade of LVL (hazard ratio [HR] = 8.5, 95% confidence interval [CI] 1.7-153.8, p = 0.0053). Higher grade of LVL carried a high risk of multiple ESCC and head and neck SCC (HNSCC) (HR = 3.7, 95% CI 2.2-6.4, p < 0.0001). Improvement in LVL significantly decreased the risk of multiple ESCC and HNSCC (HR = 0.2, 95% CI 0.04-0.7, p = 0.009). CONCLUSIONS: This is the first report indicating that field cancerization was reversible and cessation or reduction of drinking alcohol could prevent multiple squamous dysplastic lesion and multiple ESCC and HNSCC development. CLINICAL TRIALS REGISTRY NUMBER: UMIN000001676.

Posttherapy topographical nodal status, ypN-site, predicts survival of patients who received neoadjuvant chemotherapy followed by curative surgical resection for non-type 4 locally advanced gastric cancer: supplementary analysis of JCOG1004-A.

BACKGROUND: Perioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with < 10% residual tumor is a globally accepted prognosticator in LAGC patients who received neoadjuvant chemotherapy (NAC) and curative surgery. However, despite a response of the primary tumor, a significant percentage of patients dies from recurrence and identification of those at risk for relapse remains challenging. We re-estimated the value of histopathological tumor regression as a prognosticator alongside other factors, especially posttherapy topographical nodal status, ypN-site. PATIENTS AND METHODS: Individual patient data including clinicopathological variables were used from the four JCOG trials investigating NAC (JCOG0001, JCOG0002, JCOG0210, JCOG0405) for analyzing prognosticators in patients with curative surgery excluding those with type 4 AGC by univariable and multivariable Cox regression analyses. RESULTS: Among 85 patients, 5-year overall survival (OS) was 46.0% [95% confidence interval (CI) 35.0-56.4] with a median follow-up of 3.2 years. On univariable analysis, histopathological tumor regression with ≥ 10% residual tumor and ypN-site 2-3 were negatively associated with OS [≥ 10% residual tumor: hazard ratio (HR) 2.60; 95% CI 1.22-5.54; P = 0.014; ypN2-3: HR 3.59; 95% CI 1.60-8.06; P = 0.002). On multivariable analysis, only ypN-site 2-3 was predictive of OS (HR 3.67; 95% CI 1.55-8.69; P = 0.003), whereas histopathological tumor regression with ≥ 10% residual tumor was not (HR 2.24; 95% CI 0.98-5.10; P = 0.055). CONCLUSIONS: ypN-site may have greater impact on OS than histopathological tumor regression in patients who received NAC plus surgery for non-type 4 LAGC.

A case of Epstein-Barr virus-associated lymphoepithelioma-like carcinoma of the colon.

Lymphoepithelioma-like carcinoma is a poorly differentiated carcinoma with prominent lymphoid infiltration occurring in various organs but is exceedingly rare in the colorectal region. This malignancy is frequently associated with Epstein-Barr virus (EBV). Here we report a case of EBV-associated lymphoepithelioma-like carcinoma of the cecum in an 84-year-old male who presented with occult blood. In situ hybridization for EBV-encoded small RNAs (EBER) in an endoscopic submucosal dissection specimen showed that the tumor consisted of EBER-negative well-differentiated tubular adenocarcinoma and EBER-positive lymphoepithelioma-like carcinoma. Real-time PCR detected 7.16 copies of the EBV genome per cell in a sample microdissected from the latter component. Genotyping analysis demonstrated EBV genotype 1, and viral protein/transcript expression in the tumor showed EBV latency I. Expression of Ephrin receptor A2, a recently reported receptor for EBV, was demonstrated in the tumor cells by immunohistochemistry. To our knowledge, this is the first report of lymphoepithelioma-like carcinoma in the colorectal region showing a definite association with EBV infection.

Randomised comparison of postpolypectomy surveillance intervals following a two-round baseline colonoscopy: the Japan Polyp Study Workgroup.

OBJECTIVE: To assess whether follow-up colonoscopy after polypectomy at 3 years only, or at 1 and 3 years would effectively detect advanced neoplasia (AN), including nonpolypoid colorectal neoplasms (NP-CRNs). DESIGN: A prospective multicentre randomised controlled trial was conducted in 11 Japanese institutions. The enrolled participants underwent a two-round baseline colonoscopy (interval: 1 year) to remove all neoplastic lesions. Subsequently, they were randomly assigned to undergo follow-up colonoscopy at 1 and 3 years (2-examination group) or at 3 years only (1-examination group). The incidence of AN, defined as lesions with low-grade dysplasia ≥10 mm, high-grade dysplasia or invasive cancer, at follow-up colonoscopy was evaluated. RESULTS: A total of 3926 patients were enrolled in this study. The mean age was 57.3 (range: 40-69) years, and 2440 (62%) were male. Of these, 2166 patients were assigned to two groups (2-examination: 1087, 1-examination: 1079). Overall, we detected 29 AN in 28 patients at follow-up colonoscopy in both groups. On per-protocol analysis (701 in 2-examination vs 763 in 1-examination group), the incidence of AN was similar between the two groups (1.7% vs 2.1%, p=0.599). The results of the non-inferiority test were significant (p=0.017 in per-protocol, p=0.001 in intention-to-treat analysis). NP-CRNs composed of dominantly of the detected AN (62%, 18/29), and most of them were classified into laterally spreading tumour non-granular type (83%, 15/18). CONCLUSION: After a two-round baseline colonoscopy, follow-up colonoscopy at 3 years detected AN, including NP-CRNs, as effectively as follow-up colonoscopies performed after 1 and 3 years.

Long-term outcome of endoscopic resection for intramucosal esophageal squamous cell cancer: a secondary analysis of the Japan Esophageal Cohort study.

BACKGROUND: Prospectively collected long-term data of patients undergoing endoscopic resection for superficial esophageal squamous cell carcinoma (ESCC) are limited. The aim of this study was to determine the prospectively collected long-term outcomes of endoscopic resection for ESCC as a secondary analysis of the Japan Esophageal Cohort (JEC) study. METHODS: Patients who underwent endoscopic resection of intramucosal ESCC at 16 institutions between September 2005 and May 2010 were enrolled in the JEC study. All patients underwent endoscopic examination with iodine staining at 3 and 6 months after resection, and every 6 months thereafter. We investigated clinical courses after endoscopic resection, survival rates, and cumulative incidence of metachronous ESCC. RESULTS: 330 patients (mean age 67.0 years) with 396 lesions (mean size 20.4 mm) were included in the analysis. Lesions were diagnosed as high-grade intraepithelial neoplasia in 17.4 % and as squamous cell carcinoma in 82.6 % (limited to epithelium in 28.4 %, to lamina propria in 55.4 %, and to muscularis mucosa in 16.2 %). En bloc resection was achieved in 291 (73.5 %). The median follow-up period was 49.4 months. Local recurrences occurred in 13 patients (3.9 %) and were treated by endoscopic procedures. Lymph node metastasis occurred in two patients (0.6 %) after endoscopic resection. The 5-year overall, disease-specific, and metastasis-free survival rates were 95.1 %, 99.1 %, and 94.6 %, respectively. The 5-year cumulative incidence rate of metachronous ESCC was 25.7 %. CONCLUSIONS: Our study demonstrated that endoscopic resection is an effective treatment for intramucosal ESCC, with favorable long-term outcomes.

Effect of double-layer structure in intramucosal gastric signet-ring cell carcinoma on lymph node metastasis: a retrospective, single-center study.

BACKGROUND: Among all types of gastric cancer (GC), signet-ring cell carcinoma (sig-GC) accounts for 4-17% of cases. The prognosis of early sig-GC is relatively good, with the 5-year survival rate at 99.7%. However, the correlation between histological features and lymph node metastasis (LNM) among pT1a (M) sig-GC remains unclear. Sig-GC often exhibits a double-layer structure (DLS) in the intramucosal layer, demonstrating functional differentiation into the normal gastric gland. Assumedly, the loss of the differentiation makes the DLS deranged, accounting for the occurrence of submucosal invasion and LNM. This study aimed to assess the proportion of DLS, to elucidate the correlation between histological features (including DLS) and LNM status, and to determine the LNM-negative condition in pT1a (M) sig-GC. METHODS: We reviewed the pathological data of 310 patients with 310 intramucosal sig-GCs who received gastrectomy with lymph node dissection. Immunohistochemistry was performed on all specimens to evaluate the presence of DLS. Furthermore, we review the clinicopathological features, including tumor size, lymphovascular invasion (LVI), ulceration (UL), and DLS results, and then statistically analyze the correlation between these features and LNM status. RESULTS: Overall, 129 pT1a (M) sig-GCs (42%) were DLS present. The univariate analysis revealed that "Tumor size > 20 mm", "UL present", and "DLS absent" were significant risk factors of LNM. The multivariate logistic regression analysis revealed only "DLS absent" as statistically significant. CONCLUSIONS: "DLS absent" is a risk factor of LNM detected by the multivariate analysis. In pT1a (M), LVI absent, UL absent, tumor size > 20 mm, sig-GC, no LNM occurred in "DLS present" cases.

Clinicopathological characteristics of non-ampullary duodenal tumors and their phenotypic classification.

The tumorigenesis of non-ampullary duodenal epithelial tumors (NADETs) might be different between the oral and anal sides of Vater's papilla. We conducted an immunohistological review to elucidate the clinicopathological features according to the tumor location and phenotypic classification. A review of an institutional database identified 121 patients with 125 superficial NADETs. NADETs were histologically evaluated and classified into the intestinal or gastric type based on immunohistochemical analysis. Clinicopathological factors were compared based on the tumor location and phenotype. Logistic regression analysis was performed to identify independent predictors for gastric-type NADETs. According to location analysis, the mucin phenotype was significantly different (oral side, intestinal-type 64.8%, gastric-type 35.3%; anal side, intestinal-type 87.3%, gastric-type 12.7%; P < 0.01). Although the incidence of adenoma was significantly predominant in the intestinal type (75.3%), most gastric-type NADETs were cancerous (64.3%). Notably, most gastric-type NADETs were adenocarcinomas even when the tumor size was ≤0 mm. In multivariate analysis, tumor location on the oral side (odds ratio [OR], 4.42), villous structure (OR, 6.44), and low tumor gland density (OR, 9.49) were independent predictors of gastric-type tumors. Gastric-type NADETs significantly differ from intestinal-type NADETs in terms of tumor location, morphology, and biology.

Can the Ki-67 Labeling Index in Biopsy Specimens Predict the World Health Organization Grade of Rectal Neuroendocrine Tumors?

BACKGROUND: Being grade 2 is a known risk factor for metastasis in rectal neuroendocrine tumors (R-NETs). We aimed to identify the efficacy of the Ki-67 labeling index (LI) in endoscopic biopsy specimens to predict the World Health Organization (WHO) grade of R-NETs. METHODS: A total of 59 patients with 60 R-NETs (43 WHO grade 1 and 17 WHO grade 2), treated between October 2002 and December 2014, were retrospectively evaluated. The patients included in the study underwent biopsies followed by endoscopic submucosal resection with a ligation device, trans-anal full-thickness surgical resection, or radical surgery with lymph node dissection. The Ki-67 LI in the biopsy and resected specimens were compared between the 2 tumor grade groups, and the diagnostic sensitivity, specificity, and positive and negative predictive values for the detection of WHO grade 2 tumors were evaluated. RESULTS: The sensitivity, specificity, and positive and negative predictive values of the Ki-67 LI in biopsy specimens for predicting grade 2 tumors were 53% (9 of 17), 95% (41 of 43), 100% (9 of 9), and 87% (41 of 47), respectively. Pearson's rank correlation coefficient between the Ki-67 LI in the biopsy and resected specimens was 0.92. CONCLUSIONS: The Ki-67 LI of the biopsy specimen is useful for determining the appropriate treatment for R-NETs.

Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck.

BACKGROUND & AIMS: Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. METHODS: We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. RESULTS: Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. CONCLUSIONS: Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.

Can positron emission tomography detect colorectal adenomas and cancers?

BACKGROUND AND AIM: Fluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography (PET) is effective and less invasive than other modalities used to diagnose tumors, including colorectal cancer (CRC). However, the detectability of adenomas and CRCs, especially in the early stages, is unclear. METHODS: We evaluated the records of 2323 consecutive eligible patients who underwent both a total colonoscopy (TCS) and PET between October 2002 and September 2012 at a tertiary cancer center. The PET findings were verified by TCS performed independently within 1 year. Target lesions were defined as CRCs and adenomas that were 6 mm or larger in size. RESULTS: Total colonoscopy detected 532 target lesions ≥ 6 mm in size: 56 T2-T4 CRCs, 39 T1 CRCs, 223 advanced adenomas, and 214 low-grade adenomas. Of the 532 lesions, 216 (40.6%) were PET positive. Of the 369 cases with positive uptakes, PET detected target lesions in the matched segments for 58.5% (216/369). Sensitivity of PET to T2-T4 CRCs, T1 CRCs, advanced adenomas, and low-grade adenomas was 92.9%, 79.5%, 50.7%, and 9.3%, respectively. PET could detect 76.5% (13/17) of T1 CRCs whose size is 10 to 19 mm and 85.0% (17/20) of T1 CRCs equal or larger than 20 mm. The multivariate analysis excluding T2-T4 CRCs showed malignant histology, larger size, protruded lesions, villous histology, and lesions in distal colon were significant factors. CONCLUSIONS: Sensitivity of PET for detecting T2-T4 and even T1 cancers are promising. However, sensitivity of PET to adenomas, even advanced adenomas, is limited.

Risk factors for lymph node metastasis and long-term outcomes of patients with early gastric cancer after non-curative endoscopic submucosal dissection.

BACKGROUND: The long-term outcomes after non-curative gastric endoscopic submucosal dissection (ESD) are still unknown. We aimed to clarify the pathological risk factors for lymph node metastasis (LNM) of early gastric cancer (EGC) and the long-term outcomes among patients who were judged to have had non-curative ESD. METHODS: From September 2002 to December 2012, 506 patients who were judged to have had non-curative gastric ESD were enrolled and classified into two groups: (1) those who subsequently underwent additional surgical resection (surgical group, n = 323) and (2) those followed up without additional surgical resection (nonsurgical group, n = 183). We analyzed pathological risk factors for LNM of EGC in the surgical group. Additionally, we compared long-term outcomes in the two groups. RESULTS: LNM was found pathologically in 9.3 % of the surgical group (30/323) at the additional surgical resection after non-curative ESD. In the multivariate logistic regression analysis, lymphovascular invasion (LVI) was an independent risk factor for LNM in the surgical group (odds ratio 8.57, 95 % confidence interval 2.76-38.14, P < 0.0001). The 5-year cause-specific survival rate was similar in the surgical and nonsurgical groups (98.7 and 96.5 %, respectively; log-rank test, P = 0.07). In contrast, the 5-year cause-specific survival rate of patients with LVI in the surgical group was better than that in the nonsurgical group (98.2 and 79.1 %, respectively; log-rank test, P < 0.0001). CONCLUSIONS: A detailed assessment of LVI is essential to the pathological evaluation of endoscopically resected specimens. An additional surgical resection should be strongly recommended for patients with LVI.

A case of gastric-type adenoma with chief cell and parietal cell differentiation surrounded by complete intestinal metaplasia.

A man in his 70s received Helicobacter pylori eradication therapy after endoscopic submucosal dissection (ESD) of the stomach. A small, yellowish, protuberant lesion was later observed on the anterior wall of the lower body of the stomach on surveillance esophagogastroduodenoscopy. Narrow band imaging-magnified endoscopy showed an irregular pit and net-like vascular pattern, with the background mucosa having a light blue crest pattern. A biopsy was performed, which led to a diagnosis of adenoma with a gastric phenotype, so repeat ESD was performed. The freshly resected specimen showed a small, protuberant, flat lesion with a clear margin, and hematoxylin and eosin staining showed mild architectural and nuclear atypia. The shape of the atypical gland was similar to that of a fundic gland. MUC5AC, MUC6, pepsinogen A, and H+/K+ ATPase expressions were positive, and CD10 expression was negative, indicating that this tumor could not only differentiate to mucous neck cells but also to chief cells, parietal cells and foveolar epithelium. Therefore, this 4-mm tumor was diagnosed as a type 0-IIa tubular adenoma with fundic gland differentiation. The background mucosa showed complete intestinal metaplasia. Traditionally, gastric-type adenoma has been defined as the pyloric gland-type, but our case had a fundic gland phenotype. Therefore, a new fundic-gland adenoma subtype should be considered in this case.

Preoperative indicators of failure of en bloc resection or perforation in colorectal endoscopic submucosal dissection: implications for lesion stratification by technical difficulties during stepwise training.

BACKGROUND AND AIMS: The technical difficulties inherent in endoscopic submucosal dissection (ESD) for colorectal neoplasms may result in the failure of en bloc resection or perforation. The aim of this retrospective study was to assess the predictors of en bloc resection failure or perforation by using preoperatively available factors. METHODS: Between September 2002 and March 2013, 716 colorectal ESDs in 673 consecutive patients were performed at a tertiary cancer center. Patient characteristics, tumor location, tumor type, colonoscopy-related factors, and endoscopist experience were assessed based on a prospectively recorded institutional ESD database. Logistic regression analysis was performed to identify predictors of failure of en bloc resection or perforations, with subgroup analyses of ESDs performed by endoscopists less experienced in colorectal ESD (<40 cases) and for colonic lesions only. RESULTS: On multivariate analysis, independent predictors of failure of en bloc resection or perforations were the presence of fold convergence (odds ratio [OR] 4.4; 95% confidence interval [95% CI], 1.9-9.9), protruding type (OR 3.6; 95% CI, 1.8-7.1), poor endoscope operability (OR 3.5; 95% CI, 1.8-6.9), right-sided colonic lesions (OR 3.0; 95% CI, 1.5-6.3 vs rectal lesions), left-sided colonic lesions (OR 3.2; 95% CI, 1.7-6.3, vs rectal lesions), the presence of an underlying semilunar fold (OR 2.1; 95% CI, 1.3-3.6), and a less-experienced endoscopist (OR 2.1; 95% CI, 1.3-3.6). Among less-experienced endoscopists, colonic lesions were independent predictors (right-sided colonic lesions 8.1; 95% CI, 2.9-25.1; left-sided colonic lesions 8.1; 95% CI, 2.5-28.3 vs rectal lesions). For colonic lesions, the presence of fold convergence (OR 3.7; 95% CI, 1.6-8.6), poor endoscope operability (OR 3.6; 95% CI, 1.8-7.2), a less-experienced endoscopist (OR 3.0; 95% CI, 1.7-1.8), and the presence of an underlying semilunar fold (OR 2.7; 95% CI, 1.5-4.7) were identified predictors. CONCLUSION: This study successfully identified predictors of en bloc resection failure or perforation. Understanding these indicators could help to accurately stratify lesions according to technical difficulty and to appropriately select endoscopists.

Incidence of lymph node metastasis in intramucosal gastric cancer measuring 30 mm or less, with ulceration; mixed, predominantly differentiated-type histology; and no lymphovascular invasion: a multicenter retrospective study.

BACKGROUND: Intramucosal gastric cancer, ≤3 cm (≤30 mm) with ulceration, and mixed histology (predominantly differentiated), was previously considered curative after endoscopic resection, and additional surgery was thought to be unnecessary. However, as the evidence base for these criteria remains insufficient, the Japanese Gastric Cancer Treatment Guidelines, ver. 3 (2010) specify that this pathology should be considered noncurative and recommend additional surgery. We report the frequency of lymph node metastasis in patients with these conditions based on a multicenter study. METHODS: Of patients with early gastric cancer who underwent gastrectomy with lymph node dissection, those with a mixed, predominantly differentiated tumor type, ulceration, a tumor diameter ≤3 cm, and no lymphovascular invasion were entered into this study. RESULTS: Four hundred and seven patients met the criteria, 21 of whom were excluded owing to a lack of available information. Thus, a total of 386 patients were included in the analysis, from 37 of the 42 member institutions. The mean study duration was 125 months. The most common combination of mixed histology was tub2 + por (67 %). None of the 386 patients had lymph node metastasis (95 % confidence interval, 0-0.8 %). CONCLUSION: The results of this retrospective study indicate that the risk of lymph node metastasis was less than 1 % among patients with the criteria defined here, considered to be criteria for noncurative resection as per the current guidelines, and suggest that observation alone without additional surgery may result in a good outcome.

The Ki-67 labeling index and lymphatic/venous permeation predict the metastatic potential of rectal neuroendocrine tumors.

BACKGROUND: Endoscopic resection has been used to treat small rectal neuroendocrine tumors (NETs). However, the indication for additional surgery after endoscopic resection is unclear. The aim of this study was to identify risk factors for rectal NET metastasis and to determine the indication for additional surgery. METHODS: Fifty-five patients with a total of 57 rectal NETs, treated between October 2003 and January 2013, were retrospectively divided into metastatic (11 lesions) and non-metastatic (46 lesions) groups. Tumor size, central depression, invasion depth, lymphatic and venous permeation, mitotic activity, nuclear abnormality, Ki-67 labeling index, and World Health Organization grading classification (G1 or G2) were compared between the groups. Patients underwent endoscopic submucosal resection with a ligation device, transanal full-thickness surgical resection, or radical surgery. RESULTS: By univariate analysis, the odds ratios (OR) for a Ki-67 labeling index >3.0 %, positive lymphatic or venous permeation, World Health Organization grading classification G2, tumor size >10 mm, submucosal invasion >4000 µm, and central depression were 120 (P < 0.001), 67.6 (P < 0.001), 58.7 (P < 0.001), 9.8 (P = 0.0037), 6.8 (P = 0.012), and 5.7 (P = 0.018), respectively. Multivariate logistic regression analyses showed that vascular permeation (OR 111; P = 0.006) and a Ki-67 labeling index >3.0 % (OR 88; P = 0.012) were independent risk factors for metastasis. CONCLUSIONS: The Ki-67 labeling index and lymphatic/venous permeation were reliable predictors of rectal NET metastases.

A three-tier classification system based on the depth of submucosal invasion and budding/sprouting can improve the treatment strategy for T1 colorectal cancer: a retrospective multicenter study.

More than 85% of patients with T1 colorectal cancer have no lymph node metastasis and can be cured by endoscopic resection. To avoid unnecessary surgery after complete endoscopic resection, accurate histologic methods for evaluating resected specimens are needed to discriminate those at high risk for lymph node metastasis. A retrospective multi-institutional, cross-sectional study of 806 T1 colorectal cancer patients was conducted. A budding/sprouting score was incorporated for predicting lymph node metastasis in addition to other parameters, including the depth of submucosal invasion, histologic grade, and lymphovascular invasion. Lymph node metastasis was detected in 97 patients. Independent predictors of lymph node metastasis by multivariate analysis were depth of submucosal invasion ≥1000 µm (odds ratio (95% confidence interval)=5.56 (2.14-19.10)) and high-grade budding/sprouting (3.14 (1.91-5.21)). Among lesions with a depth of submucosal invasion ≥1000 µm, lymph node metastasis was detected in 59 (29%) of 207 patients with high-grade budding/sprouting, and in 34 (9%) of 396 with low-grade budding/sprouting. Lymph node metastasis was detected in only 4 (2%) of 203 lesions with a depth of submucosal invasion <1000 µm. Of these four tumors, three invaded lymphatic and/or venous vessels. Thus, the risk for lymph node metastasis can be classified into three groups: high risk with a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting, intermediate-risk with a depth of submucosal invasion ≥1000 µm and low-grade budding/sprouting, and low-risk with a depth of submucosal invasion <1000 µm. These findings revealed that a depth of submucosal invasion ≥1000 µm and high-grade budding/sprouting are powerful predictive parameters for lymph node metastasis in T1 colorectal cancer. This three-tier risk classification system will facilitate the decision for additional major surgery for T1 colorectal cancer patients after successful endoscopic treatment.