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BackgroundEndocytoscope systems (ECS) can visualize cellular nuclei of the mucosa of the gastrointestinal tract and are predicted to provide real-time microscopic diagnosis. However, their practical diagnostic performance remains unclear. Therefore, we conducted a multicenter prospective study to evaluate the visualization of superficial esophageal neoplasm in vivo using an ECS, and its diagnostic capability.MethodsThe study target was histologically confirmed squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN). An integrated ECS was used to obtain ECS images. In each patient, three ECS images of cancerous and corresponding noncancerous regions were selected for evaluation. A pathological review board of five certified pathologists made the final diagnosis of the images. The primary endpoint was the sensitivity of ECS diagnosis by pathologists.ResultsECS images of 68 patients were assessed: 42 lesions were mucosal SCC, 13 were submucosal SCC, and 13 were HGIN. The rate of assessable images was 96% (95% CI 87.6–99.1). The sensitivity of ECS diagnosis by pathologists was 88% (95% CI 77.2–94.5).ConclusionsECS can provide high-quality images of cancerous lesions and a high diagnostic accuracy by pathologists, and could be useful for real-time endoscopic histological diagnosis of SCC and HGIN.Trial registrationThe UMIN Clinical Trials Registry Identification Number: 000004218

Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands. About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Purpose Submucosal invasion depth (SID) in colorectal carcinoma (CRC) is an important factor in estimating risk of lymph node metastasis, but can be difficult to measure, leading to inadequate or over-extensive treatment. Here, we aimed to clarify the practical aspects of measuring SID in T1 CRC. Methods We investigated 568 T1 CRCs that were resected surgically at our hospital from April 2001 to December 2013, and relationships between SID and clinicopathological factors, including the means of measurement, lesion morphology, and lymph node metastasis. Results Of these 568 lesions, the SID was ≥1000 μm in 508 lesions. SIDs for lesions measured from the surface layer were all ≥1000 μm. Although lesions with SIDs ≥1000 μm were associated with significantly higher levels of unfavorable histologic types and lymphovascular infiltration than shallower lesions, a depth of ≥1000 μm was not a significant risk factor for lymph node metastasis (LNM) (6.7 vs. 9.8 %; P  = 0.64), and no lesions for which the sole pathological factor was SID ≥1000 μm had lymph node metastasis. Protruded lesions showed deeper SIDs than other types. Conclusions Although we found several problems of measuring SID in this study, we also found, surprisingly, that SID is not a risk factor for lymph node metastasis, and its measurement is not needed to estimate the risk of lymph node metastasis.

BackgroundOur previous studies have shown the diagnostic utility of a newly developed dual-focus endoscope with narrow-band imaging (DF-NBI) and simplified dyad criteria for detection of superficial esophageal squamous cell carcinoma (SESCC). This clinical trial aimed to study the diagnostic efficacy of DF-NBI with dyad criteria for detecting SESCC compared to white light imaging (WLI).MethodsThis was a single-arm prospective comparative trial. We enrolled 170 consecutive high-risk patients for esophageal squamous cell carcinoma. Patients were initially examined with WLI by one independent endoscopist and then the other performed DF-NBI blinded to the WLI diagnosis to avoid a carry-over effect. Lesions showing proliferation and/or various shapes of intrapapillary capillary loops (IPCL) under DF-NBI (i.e., dyad criteria) were endoscopically diagnosed as SESCC including high-grade intraepithelial neoplasia. The primary endpoint was sensitivity of WLI and DF-NBI for detecting SESCC. The secondary endpoints were the diagnostic performance (i.e., specificity and accuracy) and inter/intra-observer concordance of DF-NBI with dyad criteria.ResultsA total 77 SESCCs were detected. The sensitivity of DF-NBI for SESCC was significantly higher than that of WLI (91% vs. 51%, P < 0.001). The specificity and accuracy of WLI and DF-NBI using dyad criteria were 100% vs. 84%, and 86% vs. 86%, respectively. Various shapes and proliferation of IPCL showed the highest value in inter-observer and intra-observer agreements (κ = 0.77 and 0.82, respectively).ConclusionDF-NBI combined with dyad criteria may be a promising technique with a high sensitivity for diagnosis of SESCC and high inter/intra-observer agreement.

Objectives A “resect‐and‐discard” strategy has been proposed for diminutive adenomas in the colorectum. However, this strategy is sometimes difficult to implement because of the lack of confidence in differentiating low‐grade adenoma (LGA) from advanced lesions such as high‐grade adenoma or carcinoma. To perform real‐time precise diagnosis of LGA with high confidence, we assessed whether endocytoscopy (EC) diagnosis, considering normal pit‐like structure (NP‐sign), an excellent indicator of LGA, could have additional diagnostic potential compared with conventional modalities. Methods All the neoplastic lesions that were observed by non‐magnifying narrow‐band imaging (NBI), magnifying NBI (M‐NBI), magnifying pit pattern, and EC prior to pathological examination between 2005 and 2018 were retrospectively investigated. The neoplastic lesions were classified into two categories: LGA and other neoplastic lesions. We assessed the differential diagnostic ability of EC with NP‐sign between LGA and other neoplastic lesions compared with that of NBI, M‐NBI, pit pattern, and conventional EC in terms of sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC). Results A total of 1376 lesions from 1097 patients were eligible. The specificity (94.9%), accuracy (91.5%), and area under the receiver operating characteristic curve (0.95) of EC with NP‐sign were significantly higher than those of NBI, M‐NBI, pit pattern, and conventional EC. Conclusions EC diagnosis with NP‐sign has significantly higher diagnostic performance for predicting colorectal LGA compared with the conventional modalities and enables stratification of neoplastic lesions for “resect‐and‐discard” with higher confidence.

Background Pancreatic cancer is one of the most aggressive digestive cancers. The tumor expression of thrombomodulin (TM) is correlated with favorable prognosis in several types of cancer. However, this correlation has not been confirmed in hepato‐pancreato‐biliary cancer. The aim of this study was to evaluate the prognostic value of TM expression in resected pancreatic ductal adenocarcinoma. Methods The data of patients who underwent pancreatic resection for pancreatic invasive ductal adenocarcinoma were obtained from a prospectively maintained database. A total of 131 patients were included. Paraffin sections of tumor tissues were stained immunohistochemically using TM antibody. The patients were divided into two groups: the TM‐positive or TM‐negative group. Results The specimens were TM‐positive in 72 cases. TM expression was a significant factor of favorable prognosis in univariate analysis for disease‐free (DFS) and overall survival (OS). The median OS in the TM‐positive patients was 32.9 mo, which was better than the 20.0 mo in TM‐negative patients (P =.006). TM positivity retained its significance on multivariate analysis for DFS (hazard ratio [HR] 0.651, 95% confidence interval [CI] 0.433–0.979, P =.039) and OS (HR 0.569, 95% CI 0.376–0.862, P =.008). Conclusions The tumor expression of TM is a favorable factor for OS in resected pancreatic invasive ductal adenocarcinoma. We found that thrombomodulin (TM) expression was strongly correlated with cancer prognosis and lymphatic invasion. TM expression inhibited cancer recurrence and translymphatic cancer metastasis. TM expression might be a novel target for developing treatment strategies in pancreatic cancer.

Background and Aims: In gastrointestinal neuroendocrine tumors (GI-NETs), tumor size and grading based on cellular proliferative ability indicate biological malignancy but not necessarily clinically efficient prognostic stratification. We analyzed tumor size- and grading-based prevalence of lymphovascular invasion in GI-NETs to establish whether these are true biological malignancy indicators. Methods: We included 155 cases (165 lesions), diagnosed histologically with GI-NETs, that had undergone endoscopic or surgical resection. Patient age, sex, method of treatment, tumor size, invasion depth, lymphovascular invasion positivity according to Ki-67 index-based neuroendocrine tumor grading, distant metastases, and outcome were evaluated. The primary endpoints were the prevalence of lymphovascular invasion according to tumor size and grading. Results: Overall, 24.8% were positive for lymphovascular invasion. There was a high rate of lymphovascular invasion positivity even among grade 1 cases (22.8%). The rate of lymphovascular invasion was 3.4% for grade 1 cases <5 mm, with a lymphovascular invasion rate of 8.7% for those 5–10 mm. Lymphovascular invasion ≤10% required a tumor size ≤8 mm, and lymphovascular invasion ≤5% required a tumor size ≤6 mm. A cutoff of 6 mm was identified, which yielded a sensitivity of 79% and a specificity of 63%. Even small GI-NETs grade 1 of the whole GI tract also showed positive for lymphovascular invasion. Conclusions: GI-NETs ≤10 mm had a lymphovascular invasion prevalence exceeding 10%. The lymphovascular invasion impact in GI-NET development is incompletely understood, but careful follow-up, including consideration of additional surgical resection, is crucial in cases with lymphovascular invasion.

In contrast to most colorectal carcinomas arising from pedunculated or sessile protruded adenomas, submucosal-invasive (pT1) colorectal carcinoma exhibiting a depressed surface (hereinafter, \"depressed colorectal carcinoma,\" identified by means of high-definition endoscopy) is considered to be derived from depressed precursors. We hypothesized that depressed colorectal neoplasms have unique clinicopathological features different that are different from those of protruded and flat colorectal neoplasms. We classified 27,129 colorectal neoplasms (909 pT1 carcinomas and 26,220 adenomas) resected between 2001 and 2017 into depressed (211 carcinomas and 109 adenomas), flat (304 carcinomas and 11,246 adenomas), and protruded subtypes (394 carcinomas and 14,865 adenomas) and compared their clinicopathological features. As exploratory analyses of pT1 carcinomas, we conducted whole-exome sequencing for 19 depressed and 8 protruded subtypes and RNA sequencing for 8 depressed and 8 protruded subtypes. pT1 carcinomas were more common in depressed lesions (66%) than in protruded (2.6%) and flat lesions (2.6%) (P < 0.001). Compared with nondepressed pT1 carcinomas, depressed pT1 carcinomas were positively correlated with lymphovascular invasion, tumor budding, and massive submucosal invasion and inversely correlated with the presence of an adenoma component (all P < 0.001). Depressed adenomas were more likely to contain high-grade dysplasia than nondepressed adenomas (49% vs 11%, P < 0.001). A KRAS mutation was observed only in one of the 19 depressed pT1 carcinomas. Relative to protruded carcinomas, depressed carcinomas generally exhibited higher expression of genes related to angiogenesis and epithelial-mesenchymal transition. Depressed colorectal neoplasms may harbor a unique combination of malignant histopathological phenotypes and molecular features.

Lymph node metastasis significantly influences the management of patients with colorectal carcinoma. It has been observed that the biology of colorectal carcinoma differs by location. The aim of the current study was to retrospectively compare the clinicopathological characteristics of patients with colon and rectal T1 carcinomas, particularly their rates of lymph node metastasis. Of the 19,864 patients who underwent endoscopic or surgical resection of colorectal neoplasms at Showa University Northern Yokohama Hospital, 557 had T1 surgically resected carcinomas, including 457 patients with colon T1 carcinomas and 100 patients with rectal T1 carcinomas. Analysed clinicopathological features included patient age, gender, tumor size, morphology, tumor budding, invasion depth, vascular invasion, histological grade, lymphatic invasion and lymph node metastasis. Rectal T1 carcinomas were significantly larger than colon T1 carcinomas (mean ± standard deviation: 23.7±13.1 mm vs. 19.9±11.0 mm, P<0.01) and were accompanied by significantly higher rates of vascular invasion (48.0% vs. 30.2%, P<0.01). Significant differences were not observed among any other clinicopathological factors. In conclusion, tumor location itself was not a risk factor for lymph node metastasis in colorectal T1 carcinomas, even though on average, rectal T1 carcinomas were larger and accompanied by a significantly higher rate of vascular invasion than colon T1 carcinomas.

Background The number of patients suffering from colorectal cancer is increasing. According to Japanese guidelines, lesions with a submucosal invasive depth >1,000 μm should be treated with radical proctocolectomy. We propose and evaluate a new clinical classification for pit patterns that uses endoscopy to assess lesion depth for determination of the appropriate therapeutic approach for early colorectal cancers and adenomas. Methods Endoscopic images of colorectal adenomas and early cancer cases with type V I pit pattern, resected surgically or endoscopically from April 2002 to April 2007 at Showa University Yokohama Northern Hospital, were utilized for analysis. Each image was retrospectively analyzed for (A) pit narrowness, (B) irregular pit margins, and (C) indistinct stromal staining. Sensitivity, specificity, and predictive value were evaluated as major outcomes, using pathological results as the standard. Result In total, 186 cases were assessed. With all features considered (A, B, and C), the sensitivity, specificity, and positive and negative predictive values were 47.8%, 86.3%, 66.0%, and 74.2%, respectively. When limited to two features (A and B), these values were 75.3%, 81.2%, 70.2%, and 84.8%, respectively. Conclusion Our results suggest that the established criteria can, to a certain degree, distinguish between high and low irregularity in colorectal lesions with V I pit pattern indicating submucosal cancer infiltration of more or less than 1,000 μm with the clinical consequence of surgery versus endoscopic mucosal resection/endoscopic mucosal dissection.