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Background Endocytoscope 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. Methods The 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. Results ECS 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). Conclusions ECS 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 registration The UMIN Clinical Trials Registry Identification Number: 000004218

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real‐world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1–75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2–357). Adverse events occurred in 12.7%. Life‐threatening complications occurred in 0.5%, but there were no treatment‐related deaths. During a median follow‐up period of 46.1 months (range 1–113), the 3‐year overall survival rate, relapse‐free survival rate, cause‐specific survival rate, and larynx‐preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276., This is the first report on nationwide survival data and pathological criteria of superficial head and neck cancer. Transoral surgery for superficial head and neck cancer was safe and offered highly curative minimally invasive treatment preserving organs and their function. Subepithelial invasion was clinically useful predictor of recurrence after transoral surgery.

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.

Perioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with

BACKGROUND: Although pathological response is a common endpoint used to assess the efficacy of neoadjuvant chemotherapy (NAC) for gastric cancer, the problem of a low rate of concordance from evaluations among pathologists remains unresolved. Moreover, there is no globally accepted consensus regarding the optimal evaluation. A previous study based on a clinical trial suggested that pathological response measured using digitally captured virtual microscopic slides predicted patients’ survival well. However, the pathological concordance rate of this approach and its usefulness in clinical practice were unknown. AIM: To investigate the prognostic utility of pathological response measured using digital microscopic slides in clinical practice. METHODS: We retrospectively evaluated pathological specimens of gastric cancer patients who underwent NAC followed by surgery and achieved R0 resection between March 2009 and May 2015. Residual tumor area and primary tumor beds were measured in one captured image slide, which contained the largest diameter of the resected specimens. We classified patients with < 10% residual tumor relative to the primary tumorous area as responders, and the rest as non-responders; we then compared overall survival (OS) and relapse-free survival (RFS) between these two groups. Next, we compared the prognostic utility of this method using conventional Japanese criteria. RESULTS: Fifty-four patients were evaluated. The concordance rate between two evaluators was 96.2%. Median RFS of 25 responders and 29 non-responders was not reached (NR) vs 18.2 mo [hazard ratio (HR) = 0.35, P = 0.023], and median OS was NR vs 40.7 mo (HR = 0.3, P = 0.016), respectively. This prognostic value was statistically significant even after adjustment for age, eastern cooperative oncology group performance status, macroscopic type, reason for NAC, and T- and N-classification (HR = 0.23, P = 0.018). This result was also observed even in subgroup analyses for different macroscopic types (Borrmann type 4/non-type 4) and histological types (differentiated/undifferentiated). Moreover, the adjusted HR for OS between responders and non-responders was lower in this method than that in the conventional histological evaluation of Japanese Classification of Gastric Carcinoma criteria (0.23 vs 0.39, respectively). CONCLUSION: The measurement of pathological response using digitally captured virtual microscopic slides may be useful in clinical practice.

The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs), such as miR-34c, miR-124a-3, miR-129-2, and miR-137, in the gastric mucosa with and without GC, i.e., in atrophic mucosal glands without intestinal metaplasia (non-IM) and intestinal metaplastic glands (IM). DNA was isolated from non-IM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in non-IM, but not in IM. miR-129-2 methylation in non-IM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either non-IM or IM, irrespective of H. pylori infection. miR-129-2 methylation in non-IM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective for improving methylation in IM than in non-IM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development. In addition, the effects of the interventions were not uniform for each miRNA gene.

A depth of submucosal invasion (DSI) of ≥1000 μm is an important risk factor for lymph node metastasis (LNM) in patients with submucosal invasive (pT1) colorectal cancer (CRC), according to the European Society of Gastrointestinal Endoscopy and the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines. According to the latter, if the location of the muscularis mucosae in the invasive area is not confirmed, the DSI can be measured from the surface. In these cases, a ‘remaining intramucosal lesion’ (rIL), which is in the invasive area, is sometimes observed. To avoid over-measuring the DSI, we proposed a ‘modified DSI’ (mDSI), which excludes the rIL from the JSCCR DSI. We investigated the characteristics and effectiveness of the rIL and mDSI by grouping cases with polypoid growth (PG) and non-polypoid growth (NPG) histologically. Three hundred and thirty-nine consecutive patients with pT1 CRC were examined. LNM was detected in 37 cases. The distribution of the DSI and rIL was significantly higher in PG than in NPG cases (P

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.

ObjectiveTo 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).DesignA 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.ResultsA 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).ConclusionAfter 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.

Narrow-band imaging (NBI) classifications for Barrett’s esophagus have been proposed for the detection of early esophageal adenocarcinoma. We developed a simplified classification system with demonstrated high diagnostic accuracy and reproducibility among experienced endoscopists, but the feasibility of this system among novice endoscopists was unclear. In the present study, eight novice endoscopists with no experience of magnification endoscopy were asked to review 248 images of Barrett’s esophagus (72 dysplastic, 176 non-dysplastic) obtained using high-definition magnification endoscopy with NBI 6 weeks before (1st test), immediately after (2nd test), and 6 weeks after (3rd test) being taught the simplified classification system. The primary outcomes were differences in diagnostic accuracy for dysplasia among the three tests. The specificity and overall accuracy improved significantly in the 2nd vs. 1st test [97% vs. 80% (p

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.

Background: Multiple development of dysplastic squamous epithelium and squamous cell carcinoma (SCC) in the esophagus and head/neck region was associated with alcohol and cigarette use and have been explained by field cancerization phenomenon. Second primary cancer developed after curative treatment have harmful effect on patients’ quality of life and survival, however, until recently there have been no evidence-based assessment of the effects of these consumption and cessation on field cancerization. Methods: We conducted a multicentre cohort study at 16 hospitals in Japan. Patients with superficial esophageal SCC (ESCCs) who treated by endoscopic resection were registered. Dysplastic squamous epithelium in the background esophageal mucosa was evaluated by Lugol chromoendoscopy and was classified into 3 groups based on the number of Lugol-voiding lesions (LVLs) per endoscopic view: grade A, 0; grade B, 1–9; or grade C, ³10 LVLs. Lifestyle surveys were conducted using a self-administered questionnaire. Patients were counselled on the need for ceasing alcohol and cigarette consumption by physicians, and were evaluated endoscopical surveillance every 6 months. This study conforms to the STROBE guidelines Findings: Between September 12, 2005 and April 9, 2010, 331 patients with superficial ESCCs were registered. Pooled data from 1,022 healthy subjects were used for comparison. Grades of LVL were positively associated with alcohol drinking intensity, flushing reactions, smoking, high-temperature food and negatively with eating green/yellow vegetables and fruit. Secondary ESCCs and HNSCCs were significantly more prevalent in the grade C LVL group (cumulative 5-y incidences 47.1%, 95% confidence interval [CI], 38.0 to 57.2, and 13.3%, 95% CI, 8.1 to 21.5, respectively). Ceasing alcohol and cigarette use significantly reduced the development of secondary ESCCs (adjusted hazard ratios 0.47, 95% CI, 0.26 to 0.85 and 0.49, 95% CI, 0.26 to 0.91, respectively) Interpretation: Alcohol and cigarette use were closely associated with field cancerization and cessation of them significantly reduced the risk of development of second primary cancer. Funding Statement: Grant from National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour and Welfare of Japan. Declaration of Interests: The authors declared no conflict of interest. Ethics Approval Statement: This study was approved by the institutional review board at each hospital, and we obtained written informed consent from all patients. (UMIN Clinical Trials Registry ID:UMIN000001676).

We describe the case of a 70-year-old man with diabetic nephropathy undergoing hemodialysis. Four years following hemodialysis, he started taking lanthanum carbonate 1500 mg/day and lansoprazole 30 mg/day. Nine years following hemodialysis, he underwent screening esophagogastroduodenoscopy, which demonstrated the presence of the whitish cobblestone-like mucosa in the gastric corpus and multiple reddish depressed lesions with annular whitish mucosa in the antrum. With magnified narrow-band imaging endoscopy, a yellowish–white substance was observed in the villous structure, and subepithelial vessels were observed on the yellowish–white substance. Biopsies were taken from the whitish cobblestone-like mucosa of the upper corpus, a reddish depressed part of the antrum. Histologically, aggregates of cells containing amphophilic fine granular material were found in the mucosal interstitium. These cells stained positive for CD68 and were identified as histiocytes. Since he had been taking lanthanum carbonate for 5 years, we considered the possibility of histiocyte-mediated phagocytosis of lanthanum. Digital mapping via scanning electron microscopy with energy-dispersive X-ray spectrometry showed the presence of lanthanum and phosphorus in the interstitium and cytoplasm of histiocytes. The white, rough mucosa in the gastric body appeared 6 months following the commencement of lanthanum administration and still exists 3 years and 5 months after discontinuation of lanthanum.

A 60-year-old man was referred for the investigation of giant gastric folds, life-threatening anemia and hypoproteinemia. A combination of multiple endoscopic procedures derived a clinical diagnosis of protein-losing gastropathy with two gastric adenomas. After two months of alimentary therapy, the patient received total gastrectomy and fully recovered. The final pathological diagnosis was hypertrophic gastropathy of unknown origin with concomitant adenocarcinoma arising from a gastric type adenoma.

Gastric cancer frequently occurs synchronously with colorectal cancer (CRC).The aim of the present study was to assess the value of colonoscopy in patients with primariy early gastric cancer (EGC) indicated for endoscopic submucosal dissection (ESD) and to identify predictors for the risk of high-risk adenomas.A total of 130 patients with EGC, who underwent both colonoscopy and gastric ESD, and 260 controls matched for age and sex, who underwent a colonoscopy as part of our institutional health check-up program. The prevalence of high-risk adenomas in EGC patients vs. controls was evaluated.High-risk adenomas were found in 43 (33%) EGC patients and 37 (14%) controls (P0.01). Multivariate analysis showed the presence of EGC was significantly associated with high-risk adenoma [odds ratio (OR) 2.8, 95% confidence interval (CI): 1.7-4.9]. Among EGC patients, high serum CEA level (OR 2.4, 95% CI: 1.2-5.0) was an independent predictor for high-risk adenoma.Patients with EGC had a significant risk for colorectal cancer. When endoscopists detected an early gastric cancer indicated for ESD, colonoscopy should be considered for EGC patients with high serum CEA levels.

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. 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. 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

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.

The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs) such as miR-34c, miR-124a-3, miR-129-2, and miR-137 in the gastric mucosa with and without GC, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM). DNA was isolated from AM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in AM, but not in IM. miR-129-2 methylation in AM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either AM or IM irrespective of H. pylori infection. miR-129-2 methylation in AM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective in improving methylation in IM compared with AM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development.

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.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.By univariate analysis, the odds ratios (OR) for a Ki-67 labeling index3.0 %, positive lymphatic or venous permeation, World Health Organization grading classification G2, tumor size10 mm, submucosal invasion4000 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 index3.0 % (OR 88; P = 0.012) were independent risk factors for metastasis.The Ki-67 labeling index and lymphatic/venous permeation were reliable predictors of rectal NET metastases.

Background Although adenocarcinomas showing neuroendocrine differentiation or those mixed with high-grade neuroendocrine carcinoma (NEC) are sometimes encountered, composite tumors comprising neuroendocrine tumor (NET) Grade 1 and adenocarcinoma are exceedingly rare. Case presentation A 64-year-old male presented after testing positive for fecal occult blood at a medical check-up. A biopsy demonstrated the presence of a NET and endoscopic submucosal dissection was undertaken. Histologic examination revealed that a well differentiated tubular adenocarcinoma was present in addition to the NET. Furthermore, histological transition between the two tumors was evident. Accordingly, this case was considered to be a composite tumor comprising NET and adenocarcinoma. Conclusion Composite tumors consisting of NET Grade 1 and adenocarcinoma are exceedingly rare, and only a few examples have been reported hitherto.

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.

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

We assessed the clinicopathological characteristics of patients with serrated polyposis syndrome (SPS) and the incidence of advanced adenoma/colorectal cancer (CRC). We prospectively enrolled 249 consecutive patients who underwent colonoscopy at the National Cancer Center Hospital over a 6-month period. All the polyps were diagnosed using magnification colonoscopy and resection/biopsy. The enrolled patients were divided into two groups, i) those with ≥5 histologically diagnosed hyperplastic polyps (HPs) proximal to the sigmoid colon, with at least 2 polyps >10 mm in diameter and ii) those with ≥20 HPs distributed throughout the colon. The clinical characteristics of the two groups were compared, including lifestyle, family history of CRC and colonoscopic findings. HPs were identified in 228 patients, of whom 21 (8.4%) had SPS. All 21 patients had ≥20 HPs distributed throughout the colon, with none having >2 HPs ≥1 cm in diameter in the right colon. Synchronous advanced adenoma/CRC was diagnosed in 76/249 (30.5%) patients. The prevalence of advanced adenoma/CRC was higher among patients with compared to those without SPS (P=0.075). SPS was also associated with older age and higher body mass index (BMI). Our results suggested that older age and higher BMI are independent risk factors for SPS. Advanced adenoma/CRC tended to occur more frequently among patients with compared to those without SPS, although the difference was not statistically significant.

Paclitaxel–cisplatin (TC) combination is effective and well tolerated in patients with unresectable gastric cancer. We investigated the efficacy and safety of TC for locally advanced gastric cancers in a neoadjuvant setting. Patients received 2–4 courses of paclitaxel (80 mg/m2) and cisplatin (25 mg/m2) on days 1, 8, and 15 in a 4-weekly schedule, followed by radical gastrectomy. Primary endpoint was the pathological response rate: percentage of tumors in which one-third or more parts were affected. All 52 patients enrolled were eligible. Thirty-six (69.7 %) patients completed two or more courses of chemotherapy. Forty-three patients (82.7 %) underwent surgery, 33 (63.5 %) had R0 resection, and there was no treatment-related death. The pathological response was 34.6 % (95 % CI 22.0–49.1) for all registered patients; the null hypothesis of tumor response ≤10 % was rejected (p

Background There are differences in the histological diagnostic criteria for early stage gastrointestinal carcinoma between Western and Japanese pathologists. Western histological criteria of carcinoma are “presence of stromal invasion of neoplastic cells”, while Japanese criteria are “the degree of cytological and structural abnormality of neoplastic cells, regardless of stromal invasion”. The aim of the present study is to clarify and review the present status of the Western and Japanese histological criteria of early stage esophageal squamous cell carcinoma (SCC) and also to clarify their significance and accuracy. Methods Twenty-nine Polish, German, and Japanese pathologists participated in this study. A total of 18 histological slides of biopsy, endoscopic submucosal dissection (ESD), and surgical resection of esophageal squamous lesions were diagnosed using a virtual slide system. Results Most of noninvasive (intraepithelial) carcinomas diagnosed by Japanese pathologists were diagnosed as high- or low-grade dysplasia (intraepithelial neoplasia) or reactive atypia by the majority of Polish and German pathologists. Diagnoses of not only high-grade dysplasia but also low-grade dysplasia or reactive lesion by Western criteria were given for many biopsy specimens of cases in which the corresponding ESD or surgical specimens showed definite stromal invasion. Conclusion There still exist differences in the histological diagnostic criteria for early stage esophageal carcinoma between Western and Japanese pathologists. The Japanese diagnostic criteria could improve agreement of diagnoses between biopsy and resected specimens of esophageal SCC. Moreover, diagnostic approaches using Western criteria may cause delay in the early diagnosis and treatment of esophageal SCC.

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.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.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.Sensitivity of PET for detecting T2-T4 and even T1 cancers are promising. However, sensitivity of PET to adenomas, even advanced adenomas, is limited.

A simplified narrow band imaging (NBI) classification has been proposed with the objective of integrating multiple classifications of NBI surface patterns in Barrett’s esophagus (BE). Little is known about the impact of the simplified NBI classification on the diagnosis of BE when using high-definition magnification endoscopy with NBI (HM-NBI). This study aimed to evaluate (a) the reproducibility of NBI surface patterns and predicted histology and (b) the diagnostic accuracy of interpreting HM-NBI images by using the simplified NBI classification. Two hundred and forty-eight HM-NBI images from macroscopically normal areas in patients with BE were retrieved from endoscopy databases and randomized for review by four endoscopists (two experts, two non-experts). We evaluated inter- and intra-observer agreement of the interpretation of NBI surface patterns and the predicted histology (dysplasia vs. non-dysplasia), as calculated by using κ statistics, and diagnostic values of the prediction. The overall inter-observer agreements were substantial for mucosal pattern (κ = 0.73) and vascular pattern (κ = 0.71), and almost perfect for predicting dysplastic histology (κ = 0.80). The overall intra-observer agreements were almost perfect for mucosal (κ = 0.84) and vascular patterns (κ = 0.86), and predicting dysplastic histology (κ = 0.89). The mean accuracy in predicting dysplastic histology for all reviewers was 95 % (experts: 96.8 %, non-experts: 93.1 %). The simplified NBI classification has the potential to provide high diagnostic reproducibility and accuracy when using HM-NBI.

Yamaguchi T, Taniguchi H, Fujita S, Sekine S, Yamamoto S, Akasu T, Kushima R, Tani T, Moriya Y & Shimoda T (2012) Histopathology 61, 162–169 Clinicopathological characteristics and prognostic factors of advanced colorectal mucinous adenocarcinoma Aims: Mucinous adenocarcinoma (MUC) is a histological variant of colorectal adenocarcinoma. The aim of the present study was to characterize clinicopathological features and identify prognostic factors of MUCs. Methods and results: A total of 181 patients with MUC who underwent surgery between 1975 and 2003 were reviewed. The clinicopathological features of these patients were compared with those of 4125 non-MUC patients. Univariate and multivariate analyses were conducted to identify significant prognostic factors in 102 patients with pT3 or pT4 tumour who underwent curative surgery. Patients with MUCs tended to present with more advanced clinical stages. The overall 5-year survival rate of MUC patients was lower than that of non-MUC patients; however, no prognostic difference was found when patients with the same clinical stages were compared. Multivariate analysis revealed male sex, bowel obstruction and infiltrating growth type as independent prognostic factors. Five-year cancer-specific survival rates for MUC patients with ≤1, 2 and 3 risk factors identified by multivariate analysis were 95.5%, 52.1% and 0.0%, respectively (P

We recently demonstrated that overexpression of the nucleolar GTP-binding protein nucleostemin drives the fraction of genetically-defined tumor cells that exhibit markers and tumorigenic properties of tumor initiating cells. More specifically, cells that constitutively express elevated levels of nucleostemin exhibit increased TWIST expression; expression of genes that induced pluripotent stem cells; enhanced radioresistance; tumor formation, even when small numbers of cells are implanted; and an increased propensity to metastasize. An immunohistochemical analysis of cancer stem cell markers, such as nucleostemin and TWIST has not been conducted in surgically-resected esophageal squamous cell carcinomas after neoadjuvant chemotherapy. In the present study, we examined the expression of CD133, CD44, nucleostemin, guanine nucleotide-binding protein-like 3-like, and TWIST by immunohistochemistry in a series of 54 surgically-resected specimens of esophageal squamous cell carcinomas after neoadjuvant chemotherapy. We identified that high nucleostemin proportion, TWIST intensity, and advanced pathological N stage were significantly correlated with poor relapse-free survival. Together, these observations imply nucleostemin and TWIST as the predictive markers for postoperative recurrence. (Cancer Sci 2012; 103: 233–238)

Background and Aims: The results of a randomized controlled study and meta-analysis study have recently proved that Helicobacter pylori eradication has a preventive effect against the development of metachronous and primary gastric cancer. However, gastric cancer is sometimes detected after successful eradication. There is a lack of study about gastric cancers in eradicated patients. To clarify the characteristics of gastric cancers detected after H. pylori eradication, we analyzed the clinicopathological features of these cancers. Methods: The subjects were 18 early-stage gastric cancer specimens resected from 17 patients who had received successful eradication of H. pylori from February 1995 to March 2009. The control group consisted of 36 specimens from noneradicated patients with persistent H. pylori infection who were matched with the subjects in age, sex, and depth of invasion. Clinicopathological features and mucin phenotypes of gastric cancer were clinically and immunohistologically evaluated. Results: The average diameter of gastric cancer was smaller and Ki-67 index was lower in the eradication group. The morphological distribution of depression types was significantly lower in the control group. Immunohistochemical phenotyping revealed that 72.2% of the lesions in the eradicated group were complete gastric type or gastric predominant mixed type, whereas the percentages of gastric type and intestinal type in the control group were similar. Conclusion: Our findings indicate that the clinicopathological characteristics of gastric cancers detected after H. pylori eradication are different from those of gastric cancers in patients with persistent H. pylori infection. H. pylori eradication may suppress intestinalization during the development of gastric cancer.

Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen ( PSCA ), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 ( MUC1 ) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10 −13 ; odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 ( P = 1.43 × 10 −11 ; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

The application of standardized protocol by pathologists for handling, grossing, and assessing endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) specimens is critical for accurate diagnosis. To best analyze the specimen, several factors, such as maintenance of proper orientation, meticulous macroscopic examination, accurate mapping of the lesion, and appropriate morphologic diagnosis, must be considered. In Japan, general guidelines in the reporting of endoscopic, pathologic, and surgical findings of patients with gastrointestinal cancers have been used for more than 3 decades. More recently, similar universal guidelines have been developed, including the Paris and Vienna classifications, for clinical and pathologic findings, respectively. The WHO Classification of Tumors of the Digestive System (4th edition) can also provide a standardized method to classify pathologic diagnosis. These guidelines provide common terminology for the endoscopists, surgeons, and pathologists to communicate. The standard of practice for EMR and ESD reporting should always include the macroscopic diagnosis, size of the lesion, differentiation, associated findings (ie, gastritis), depth of invasion, presence of peptic ulcer or scar of a stomach lesion, margin status (horizontal and vertical), and lymphovascular/venous invasion because these features are relevant to prognosis and additional treatment decisions.

There have been few reports of the dual differentiation of different cell types within the same gastric tumor. Here, we report a rare case of poorly differentiated endocrine cell carcinoma with an associated differentiated signet ring cell population arising in the stomach. The histological appearance of the tumor by light microscopy matched the phenotype of endocrine cell carcinoma and signet ring cell differentiation with mucinous lakes. Cells with a phenotype intermediate between the two differentiated cell types were also seen in the tumor. Both the endocrine cell carcinoma and the signet ring cells were diffusely positive for chromogranin A and synaptophysin, a finding that is consistent with endocrine differentiation by immunohistochemical examination. The patient's postoperative clinical course had a poor prognosis, with aggressive tumor progression. Paraaortic lymph node recurrence was found 6 months after the operation, and the patient died of the primary disease 16 months after the surgical treatment.

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.

Extraskeletal myxoid chondrosarcomas (EMCs) are characterized histologically by a cord-like or lace-like arrangement of small round cells or short spindle cells with eosinophilic cytoplasm distributed in a rich myxoid matrix. Atypical cases of EMC have also been described, with areas of poor mucus production and high cellularity and a transition to typical EMC. Most cases of EMC harbor the chromosomal reciprocal translocation t(9;22) (q22;q12) and the resultant fused gene, Ewing sarcoma region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). Other translocations, such as those involving the NR4A3 gene, have also been noted, although these occur at a lower frequency. On this basis, we conducted a fluorescence in situ hybridization (FISH) analysis of 18 cases of EMC in which patients presented with typical or atypical (areas of high cellularity) histologic features of EMC. We used an EWSR1 probe and a newly prepared NR4A3 probe to evaluate the usefulness of FISH in the pathologic diagnosis of EMC. FISH analysis using the EWSR1 or NR4A3 probe showed split signals in 83% (15/18) of the cases, regardless of the presence of typical/atypical histologic features. Gene rearrangement of EWSR1 was noted in 72% (13/18) of the cases, and rearrangement of NR4A3 was noted in 61% (11/18) of the cases. The NR4A3 rearrangement was detected in 2 cases not carrying any EWSR1 rearrangement, as determined by reverse transcription-polymerase chain reaction. These results suggest that FISH analysis of formalin-fixed, paraffin-embedded specimens using EWSR1 and NR4A3 probes is useful and convenient and may provide an ancillary method for the diagnosis of EMC.

Purpose: We aimed to identify novel chemotherapy responsiveness biomarkers for osteosarcoma (OS) by investigating the global protein expression profile of 12 biopsy samples from OS patients. Experimental design: Six patients were classified as good responders and six as poor responders, according to the Huvos grading system. The protein expression profiles obtained by 2-D DIGE consisted of 2250 protein spots. Results: Among them, we identified 55 protein spots whose intensity was significantly different (Bonferroni adjusted p-value

Recently, the emerging role of nonpolypoid precursors of colorectal cancer has challenged the conventional polyp-cancer sequence. The impact of colonoscopy in cancer prevention depends on its reliability in the diagnosis of colorectal neoplasia when the lesion does not extend beyond the submucosa and is potentially curable. The estimation of the risk of progression is based on the prediction of histology from the morphological appearance of the lesion and includes (1) distinction between neoplastic and non-neoplastic lesions, (2) identification of different categories of non-serrated and serrated lesions, and (3) determination of the localization in the proximal or distal colon, which has an impact on the morphology and behavior of the lesion. The pragmatic classification Of superficial neoplastic lesions proposed in this text takes into account these changes and is based oil a 2-step strategy of endoscopic diagnosis with initial detection and characterization, followed by treatment implementation, Such as endoscopic resection, ablation, and Surgery

Objective: The clinical course of gastrointestinal stromal tumor (GIST) spans a wide spectrum from a curable disorder to a highly malignant disease that leads to metastasis and death. To develop prognostic modalities for GIST patients, we developed a mouse monoclonal antibody against pfetin, the prognostic value of which has been previously reported. Methods: The reactivity of the monoclonal antibody against pfetin was examined by western blotting and immunohistochemistry. Results: Western blotting demonstrated that the monoclonal antibody was specific to pfetin. The immunohistochemical study demonstrated that the 5-year disease-free survival rate was 93.2% and 94.5% for GIST patients with pfetin-positive tumors and 70.0% and 80.7% for those with pfetin-negative tumors in the 159 cases from the National Cancer Center Hospital (P , 0.0001) and in the 100 cases from Niigata University Medical and Dental Hospital (P , 0.0001), respectively. Uni- and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinico-pathological parameters examined. Conclusions: These results establish pfetin as a practical prognostic marker for GIST patients after surgery. Pfetin may also present a novel therapeutic target to prevent recurrence of GIST.