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Centrosome anomalies contribute to tumorigenesis, but it remains unclear how they are generated in lethal cancer phenotypes. Here, it is demonstrated that human microsatellite instable (MSI) and BRAFV600E-mutant colorectal cancers with a lethal rhabdoid phenotype are characterized by inactivation of centrosomal functions. A splice site mutation that causes an unbalanced dosage of rootletin (CROCC), a centrosome linker component required for centrosome cohesion and separation at the chromosome 1p36.13 locus, resulted in abnormally shaped centrosomes in rhabdoid cells from human colon tissues. Notably, deleterious deletions at 1p36.13 were recurrent in a subgroup of BRAFV600E-mutant and microsatellite stable (MSS) rhabdoid colorectal cancers, but not in classical colorectal cancer or pediatric rhabdoid tumors. Interfering with CROCC expression in near-diploid BRAFV600E-mutant/MSI colon cancer cells disrupts bipolar mitotic spindle architecture, promotes tetraploid segregation errors, resulting in a highly aggressive rhabdoid-like phenotype in vitro. Restoring near-wild-type levels of CROCC in a metastatic model harboring 1p36.13 deletion results in correction of centrosome segregation errors and cell death, revealing a mechanism of tolerance to mitotic errors and tetraploidization promoted by deleterious 1p36.13 loss. Accordingly, cancer cells lacking 1p36.13 display far greater sensitivity to centrosome spindle pole stabilizing agents in vitro. These data shed light on a previously unknown link between centrosome cohesion defects and lethal cancer phenotypes providing new insight into pathways underlying genome instability.Implications: Mis-segregation of chromosomes is a prominent feature of chromosome instability and intratumoral heterogeneity recurrent in metastatic tumors for which the molecular basis is unknown. This study provides insight into the mechanism by which defects in rootletin, a centrosome linker component causes tetraploid segregation errors and phenotypic transition to a clinically devastating form of malignant rhabdoid tumor. Mol Cancer Res; 16(9); 1385–95. ©2018 AACR.

Supplementary Table 1. Clinicopathological, immunohistochemical and molecular features of the 12 rhabdoid colorectal cancers7 Supplementary Table 2. Somatic mutations of candidate genes (15 out of 20 are reported) shared by the two rhabdoid cancers at exome sequencing Supplementary Table 3. Rhabdoid colorectal cancers (RC): molecular alterations, centrosome aberrations and ploidy Supplementary Table 4. Rhabdoid tumours of infants (RI): molecular alterations, centrosome aberrations, and ploidy Supplementary Table 5: Clinicopathologic and molecular features of classical colorectal cancers analyzed Supplementary Table 6. Sequencing and Reverse transcription PCR primers Supplementary Table 6B. SMARCB1 regions covered by the custom panel used for next-generation target sequencing Supplementary Table 7. CROCC regions covered by the custom panel used for next-generation targeted sequencing Supplementary Table 8. Antibodies employed and working conditions for immunohistochemistry, immunofluorescence or western blot analysis of tissues and cell lines Supplementary Table 9. Rhabdoid colorectal cancer reported in literature between 1993-2015

The file contains supplementary Materials and Methods

S1. Whole exome sequencing analysis of two rhabdoid colorectal cancers (RC). S2. Non-silent somatic mutations in rhabdoid tumours are enriched in centrosome-microtubule components. S3. Effect of CROCC mutations on centrosome phenotype. S4. CROCC expression profiling in classical colorectal cancers (CRCs). S5. Allelic loss at the 1p36.13 locus correlates with chromosomal instability in colorectal cancer cells. S6. Centrosome and chromosome instability in colorectal cancer cells. S7. Mitotic errors and impaired cell cycle caused by stable CROCC depletion in RKO cells. S8. Invasive behavior of colorectal cancer cells triggered by CROCC depletion. S9. Mitotic aberrations suppressed by CROCC or microtubule stabilizing agents in metastatic T84 and HT29 colorectal cancer cells.

A 22-year-old man presented with recurrent dizziness and melena. He had no remarkable medical history except for the reflux symptoms for which 18 months of proton pump inhibitor (PPI) intake was required. Gastroscopy revealed a 1-cm, blood-tinged polyp within the gastric rugae. A thickened gastric corpus was observed with a regular arrangement of collecting venules on its surface. Hyperplastic foveolar epithelium was observed in the biopsied specimens from the fundus and gastric rugae. The diagnosis after polypectomy was gastric hyperplastic polyp. Abdominal CT revealed hypertrophy only in the gastric corpus without antral involvement. Increased levels of serum pepsinogen I (>160 ng/mL), pepsinogen II (>50 ng/mL), chromogranin A (>1,800 ng/mL), and gastrin (534 pg/mL) were noted. Three months after PPI discontinuation, CT revealed improvement of the hypertrophic gastric corpus. Serum chromogranin A and gastrin levels decreased to 950.4 ng/mL and 517.0 pg/mL, respectively. Herein, we report a young, Helicobacter pylori-naive patient with prominent hyperplasia in the gastric corpus and a bleeding hyperplastic polyp after long-term PPI use.

Autoimmune gastritis is a corpus-dominant type of gastritis with positive serum anti-parietal cell antibodies (APCA) and/or anti-intrinsic factor antibodies. Serum APCA and pepsinogen (PG) assays were performed in subjects with corpus-dominant gastritis detected by endoscopy. Serum APCA was positive in five patients. All these patients were postmenopausal women (four Koreans and one Caucasian from the Russian Federation) with a mean age of 59.0±3.2 years. They displayed low PG I levels ranging from 8.1 to 18.8 ng/mL (mean, 11.4±4.8 ng/mL) and low PG I/II ratios ranging from 0.7 to 2.4 (mean, 1.2±0.7). Three of the patients were being treated for autoimmune thyroiditis. Multiple gastric neuroendocrine tumors were observed in two Helicobacter pylori (H. pylori)-naive patients with high serum gastrin levels exceeding 700 pg/mL and serum chromogranin A levels exceeding 1,000 ng/mL. In the remaining three patients, intestinal metaplasia was observed in the biopsied specimens from the antrum, suggesting a history of H. pylori infection. Our findings indicate the value of positive serum APCA findings, low serum PG I levels, and low serum PG I/II ratios in confirming autoimmune gastritis in patients showing corpus-dominant atrophy, regardless of their H. pylori infection status.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis and a lack of targeted therapy. Overexpression ofFirst, using different web-based bioinformatics platforms (TIMER 2.0, UALCAN, and GEPIA 2), the expression ofThe expression of

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

Purpose Triple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressive and metastatic behavior and the lack of available targeted therapies. Therefore, therapeutic strategies are needed to improve TNBC patient management. Recently, atezolizumab and nab-paclitaxel chemotherapy has been approved by the Food and Drug Administration for the first-line treatment of patients with locally advanced and metastatic TNBC. The programmed death-ligand 1 (PD-L1) immunohistochemical SP142 assay was also approved as a companion diagnostic device for selecting TNBC patients for atezolizumab treatment. This study aimed to evaluate and compare the analytical performance of the PD-L1 22C3/SP263 assays in comparison with the SP142 assay for ≥ 1% immune cells (ICs). Methods Immunohistochemical expression for the PD-L1 22C3/SP263 assays, in comparison with the SP142 assay, was analyzed for the ≥ 1% ICs in 95 TNBCs. Results At the 1% cut-off value, the proportions of positive cases were 52.6% for the SP142 assay in infiltrating ICs and 50.5% and 52.6% for the 22C3 and SP263 assays in tumor cells, respectively. The PD-L1 SP263 assay had the highest while the PD-L1 22C3 assay had the lowest total positive expression rate at all cut-off values. The concordance rate between the assays was highest at a 1% cut-off value and decreased when the cut-off value increased. The concordance rate between the SP142 and SP263 assays at 1% cut-off was high, while in comparison, the concordance rate between the SP142 and 22C3 assays at 1% cut-off was relatively lower. Conclusion This study demonstrates that although the 22C3 assay at a 1% cut-off value compared with the PD-L1 SP142 assay at the clinically relevant cut-off shows comparable but not interchangeable analytical performance, the analytical performance of the SP263 assay at a 1% cut-off value shows interchangeable performance with the PD-L1 SP142 assay at the clinically relevant cut-off.

KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis.

The Cancer Genome Atlas data on gastric carcinoma has identified four biologic pathways as potential drivers of gastric carcinogenesis and suggested targeted therapies based on the genomic alterations underscoring each subset. The correlation between morphology, biologic groups and their corresponding biomarkers has been eluded in several previous studies; however, a comprehensive analysis in consideration of the recent advancements has not been performed. In this study we explored the predictive value of morphology for biomarker expression and its association with protein expression based classification of gastric carcinoma. Four hundred eighty six gastric carcinomas which had been classified into protein expression-based groups formed the case cohort. Upon analysis, we found a low positive predictive value of an individual morphologic pattern for biomarker-expression, indicating that an individual morphologic pattern alone cannot predict PD-L1, Her2/neu expression and EBV- or MSI-gastric cancer. A combination approach targeting the test in certain WHO patterns can be employed for maximizing the positive predictive values. These include, PD-L1 testing in tubular, carcinoma with lymphoid stroma, undifferentiated and poorly cohesive patterns and Her2/neu testing in tubular, mixed, papillary, mucinous and solid patterns. The predictive values and morphologic associations presented here have the potential to select patients for personalized therapy.

The comparison of the genetic profiles between primary and metastatic colorectal cancer (CRC) is needed to enable the discovery of useful therapeutic targets against metastatic CRCs. We performed the targeted next generation sequencing assay of 170 cancer-associated genes for 142 metastatic CRCs, including 95 pairs of primary and metastatic CRCs, to reveal their genomic characteristics and to assess the genetic heterogeneity. The most frequently mutated gene in primary and metastatic CRCs was APC (71% vs. 65%), TP53 (54% vs. 57%), KRAS (45% vs. 44%), PIK3CA (16% vs. 19%), SMAD4 (15% vs. 14%) and FBXW7 (11% vs. 11%). The concordance in the top six frequently mutated genes was 85%, on average. The overall mutation frequencies were consistent with two sets of public data (TCGA and MSKCC). To the author’s knowledge, this is the first study to compare the genetic profiles of our cohort with that of the metastatic CRCs from MSKCC. Comparative sequencing analysis between primary and metastatic CRCs revealed a high degree of genetic concordance in the current clinically actionable genes. Therefore, the genetic investigation of archived primary tumor samples with the challenges of obtaining an adequate sample from metastatic sites appears to be sufficient for the application of cancer precision medicine in the metastatic setting.

Objectives: There are differences in each country with regards to histopathological managements of colorectal cancer (CRC), such as definition of Tis and lymphatic and venous invasion. In this study, we compared Tis and T1 CRC in Japan and Korea. Methods: We retrospectively compared various clinical characteristics of consecutive patients who had Tis and T1 CRCs and who were newly diagnosed between 2010 and 2014 at the Kyoto Prefectural University of Medicine (Japan) and the Konkuk University (Korea). Results: Three hundred and sixty-five cases of T1 cancer and 510 cases of Tis cancer from 726 Japanese and 149 Korean patients were included. The rate of Tis in Japan was higher than in Korea (59.8% vs. 51.0%, P = 0.047), according to the difference of definition of Tis. In the analyses of 365 T1 CRCs, median age was higher in Japan than Korea (67.8 ± 10.6 vs. 62.2 ± 10.1, P < 0.001). Right-sided lesions were more frequent in Japan than they were in Korea (38.7% vs. 22.2%, P < 0.001). The rates of venous and lymphatic invasion were higher in Japan than they were in Korea (venous: 18.6% vs. 1.4%, P < 0.001, lymphatic: 25.3% vs. 13.7%, P = 0.042), according to the different methods of immunohistochemical examinations used (Japan: E-HE and D2-40, Korea: ERG). Conclusions: Our study of T1 CRC showed that there were differences between Japan and Korea in tumor location, elderly incidence, and histopathological lymphatic and venous invasion. Additionally, rates of Tis were different between the two countries. In this international study for CRC, it is considered that we have to pay attention regarding the difference of histopathological definition and method in each country.

Background/Aims: Nodular gastritis (NG) is a well-known endoscopic finding observed in patients with a Helicobacter pylori infection, which may lead to invasive gastric cancer. Lymphofollicular gastritis consists of lymphoid follicles or lymphoid cell aggregates, and is common in children. The aim of this study was to identify patients with NG from those in whom gastric biopsied specimens showed lymphoid follicles and lymphoid cell aggregates. Methods: Subjects, whose gastric biopsy specimens showed lymphoid follicles or lymphoid cell aggregates, were included in this study. The inclusion criterion was that they underwent a serum pepsinogen assay on the day of upper gastrointestinal endoscopy. NG was diagnosed if the endoscopy findings revealed regular-sized, multiple, colorless subepithelial nodules. Results : Among 108 subjects who showed lymphoid follicles or lymphoid cell aggregates, 13 (12.0%) revealed NG on endoscopy, and all these subjects showed positive Giemsa staining. Patients diagnosed with NG were younger (p=0.012) and showed a female predominance (p=0.001) compared to those without NG. The mean serum pepsinogen levels were higher (p=0.001) and lymphoid follicle-dominant subjects were more common (p＜0.001) in the NG subjects than in those without NG. Logistic regression analysis revealed a younger age (p=0.041) and female gender (p=0.002) to be significant independent risk factors for NG. Conclusions: NG should be distinguished from lymphofollicular gastritis because only 12% of patients showing gastric biopsy findings of lymphoid follicles and lymphoid cell aggregates demonstrated NG on endoscopy. NG is an endoscopic finding that is more common in women and in the younger population, irrespective of the biopsy findings and gastric secretory ability.

Background: The BRAFV600E mutation in papillary thyroid carcinoma (PTC) is particularly prevalent in Korea, and a considerable number of wild-type BRAF PTCs harbor RAS mutations. In addition, subsets of other genetic alterations clearly exist, but their prevalence in the Korean population has not been well studied. Recent increased insight into noninvasive encapsulated follicular variant PTC has prompted endocrine pathologists to reclassify this entity as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP). This study analyzed the genetic alterations among the histologic variants of PTC, including NIFTP. Methods: Mutations of the BRAF and RAS genes and rearrangement of the RET/PTC1, NTRK1, and ALK genes using 769 preoperative fine-needle aspiration specimens and resected PTCs were analyzed. Results: Molecular alterations were found in 687 (89.3%) of 769 PTCs. BRAFV600E mutation (80.8%) was the most frequent alteration, followed by RAS mutation and RET/PTC1, NTRK1, and AL...

Background/Aims The presence of invasion is a diagnostic criterion of early gastric cancer (EGC) in Korea, whereas diagnosis in Japan is based on enlarged nuclei and prominent nucleoli. Moreover, the depth of invasion is the location of cancer cell infiltration in Korea, whereas it is the location of lymphovascular invasion (LVI) or cancer cell infiltration in Japan. We evaluated the characteristics of EGC with LVI to uncover the effects of different diagnostic criteria. Methods Consecutive T1-stage EGC patients who underwent complete resection were included after endoscopic or surgical resection. The presence of LVI was evaluated. Results LVI was present in 112 of 1,089 T1-stage EGC patients. LVI was associated with depth of invasion (p

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

Inspissated bile syndrome (IBS) is a rare condition in which thick intraluminal bile, including bile plugs, sludge, or stones, blocks the extrahepatic bile ducts in an infant. A 5-week-old female infant was admitted for evaluation of jaundice and acholic stool. Diagnostic tests, including ultrasound sonography, magnetic resonance cholangiopancreatography, and a hepatobiliary scan, were not conclusive. Although the diagnosis was unclear, the clinical and laboratory findings improved gradually on administration of urodeoxycholic acid and lipid emulsion containing omega-3 polyunsaturated fatty acids (PUFAs) for 3 weeks. However, a liver biopsy was suggestive of biliary atresia. This finding forced us to perform intraoperative cholangiography, which revealed a patent common bile duct with impacted thick bile. We performed normal saline irrigation and the symptom was improved, the final diagnosis was IBS. Thus, we herein report that IBS can be treated with omega-3 PUFAs as an alternative to surgical intervention.

BACKGROUND Accurate detection of significant fibrosis (fibrosis stage 2 or higher on the METAVIR scale) is important especially for chronic hepatitis B (CHB) patients with high viral loads but with normal or mildly elevated alanine aminotransferase (ALT) levels because the presence of significant fibrosis is accepted as the indication for antiviral treatment. Liver biopsy is the reference standard for diagnosing significant fibrosis, but it is an invasive procedure. Consequently, noninvasive imaging-based measurements, such as magnetic resonance elastography (MRE) or two-dimensional shear-wave elastography (2D-SWE), have been proposed for the quantitative assessment of liver fibrosis. AIM To explore MRE and 2D-SWE to identify fibrosis stage, and to compare their performance with that of serum-based indices. METHODS The study enrolled 63 treatment-naïve CHB patients with high viral loads but with normal or mildly elevated ALT levels who underwent liver biopsy before a decision was made to initiate antiviral therapy. MRE and 2D-SWE were performed, and serum-based indices, such as FIB-4 and aspartate transaminase to platelet ratio index (APRI), were calculated. The diagnostic performances of MRE, 2D-SWE, FIB-4, and APRI for assessing significant fibrosis (≥ F2) and cirrhosis (F4) were evaluated with liver histology as the reference standard, using receiver operating characteristic analyses. RESULTS The liver fibrosis stage was F0/F1 in 19, F2 in 14, F3 in 14, and F4 in 16 patients, respectively. MRE significantly discriminated F2 from F0/1 (P = 0.022), whereas 2D-SWE showed a broad overlap in distinguishing those stages. MRE showed a higher correlation coefficient value with fibrosis stage than 2D-SWE with fibrosis stage (0.869 vs 0.649, Spearman test; P < 0.001). Multivariate linear regression analyses showed that fibrosis stage was the only factor affecting the values of MRE (P < 0.001), whereas body mass index (P = 0.042) and fibrosis stage (P < 0.001) were independent factors affecting 2D-SWE values. MRE performance for diagnosing significant fibrosis was better [area under the curve (AUC) = 0.906, positive predictive value (PPV) 97.3%, negative predictive value (NPV) 69.2%] than that of FIB-4 (AUC = 0.697, P = 0.002) and APRI (AUC = 0.717, P = 0.010), whereas the performance of 2D-SWE (AUC = 0.843, PPV 86%, NPV 65%) was not significantly different from that of FIB-4 or APRI. CONCLUSION Compared to SWE, MRE might be more precise non-invasive assessment for depicting significant fibrosis and for making-decision to initiate antiviral-therapy in treatment-naïve CHB patients with normal or mildly-elevated ALT levels.

Mucosal inflammation is characterized by neutrophil and mononuclear cell infiltration. This study aimed to determine the gastric and duodenal microbiota associated with histological, endoscopic, and symptomatic gastritis. Dyspeptic adults who presented for evaluation were included. Subjects with either comorbidities or recent drug intake were excluded. Three endoscopic biopsies were obtained from the antrum, body, and duodenum. Next-generation sequencing for 16S ribosomal RNA V1&ndash, V2 hypervariable regions was performed. The correlation between the composition of microbiota and the degree of inflammatory cell infiltration, endoscopic findings, and Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) score was analyzed. In 98 included subjects, microbial communities in the antrum and body showed Bray&ndash, Curtis similarity, however, those in the duodenum showed dissimilarity. Histological and endoscopic gastritis was associated with the abundance of Helicobacter pylori and that of commensal bacteria in the stomach. The abundances of Variovorax paradoxus and Porphyromonas gingivalis were correlated with histological gastritis, but not with endoscopic or symptomatic gastritis. The total PAGI-SYM score showed a stronger correlation with the duodenal microbiota (Prevotella nanceiensis and Alloprevotella rava) than with the gastric microbiota (H. pylori, Neisseria elongate, and Corynebacterium segmentosum). Different correlations of the gastric and duodenal microbiota with histological, endoscopic, and symptomatic gastritis were observed for the first time at the species level. H. pylori-negative gastritis is not associated with endoscopic or symptomatic gastritis. Only H. pylori-induced endoscopic gastritis requires gastric cancer surveillance. Owing to the weak correlation with H. pylori, symptomatic gastritis should be assessed separately from histological and endoscopic gastritis.

ObjectiveThe current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important.MethodsWe performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations.ResultsK-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC.ConclusionThe existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP.

// Seung Eun Lee 1 , Seong-Hwan Chang 2 , Wook Youn Kim 1 , So Dug Lim 1 , Wan Seop Kim 1 , Tea Sook Hwang 1 and Hye Seung Han 1 1 Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea 2 Department of Surgery, Konkuk University School of Medicine, Seoul, Korea Correspondence to: Hye Seung Han, email: // Keywords : TERT, CTNNB1, hepatocellular carcinoma, intratumoral genetic heterogeneity, Pathology Section Received : May 05, 2016 Accepted : September 12, 2016 Published : September 19, 2016 Abstract Genetic alterations of TERT and CTNNB1 have been documented in hepatocellular carcinoma. TERT promoter mutations are the earliest genetic events in the multistep process of hepatocarcinogenesis related to cirrhosis. However, analyses of TERT promoter and CTNNB1 mutations in hepatocellular carcinoma tumor samples have not been performed in the Korean population, where hepatitis B virus-related hepatocellular carcinoma is prevalent. In order to identify the role of TERT promoter and CTNNB1 mutations in the hepatocarcinogenesis and pathogenesis of recurrent hepatocellular carcinoma, we performed the sequence analyses in 140 hepatocellular nodules (including 107 hepatocellular carcinomas), and 8 pairs of matched primary and relapsed hepatocellular carcinomas. TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions. Of 109 patients with hepatocellular carcinoma, 41 (39.0%) and 15 (14.6%) harbored TERT and CTNNB1 mutations, respectively. TERT promotermutations were significantly more frequent in hepatocellular carcinomas related to hepatitis C virus infection (5/6; 83.3%) compared to tumors of other etiologies ( P = 0.001). In two cases, discordance in TERT promoter mutation status was observed between the primary and the corresponding recurrent hepatocellular carcinoma. The two patients with discordant cases had early relapses. In conclusion, we identified TERT promoter and CTNNB1 mutations as the most frequent somatic genetic alterations observed in hepatocellular carcinoma, indicating its pivotal role in hepatocarcinogenesis. Furthermore, we suggest the possibility of intratumoral genetic heterogeneity of TERT promoter mutations in hepatocellular carcinoma as indicated by the discordance in TERT promoter mutations between primary and corresponding recurrent hepatocellular carcinoma.

Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005–2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma., Graphical Abstract

The causal role of human papillomavirus (HPV) infection has been well established in the pathogenesis of cervical cancer and precancerous lesions [1]. Among the large number of HPV genotypes identified to date, about 40 genotypes infect the mucosal lining of the human body, including the anogenital tract. Based on their epidemiological association with cervical lesions, the mucosal HPV strains are classified into high-risk (HR) and lowrisk (LR) genotypes [2,3]. The HR-HPV genotypes are detected more frequently in precancerous or cancerous cervical lesions, whereas the LR-HPV genotypes cause genital warts and are rarely associated with premalignant or malignant cervical lesions [3,4]. Although most LR- or HR-HPV infections are transient and successfully controlled by the host immune system, persistent infection with HR-HPV was highly associated with the development of high-grade dysplasia or invasive cervical cancers [5,6]. Overall, 14 HR-HPV genotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) have been identified in almost all cervical cancers worldwide [4]. Among these types, HPV 16 is the most important genotype that causes more than 50% of cervical carcinomas, followed by HPV 18 that causes 10%–15% and HPV 45 that causes approximately 7% [7]. HPV 18 is also identified in more than 35% of cervical adenocarcinomas [8]. Therefore, detecting HR-HPV in cervical samples is an important ancillary test for screening cervical lesions [9]. Furthermore, HPV testing has been shown to have a high negative predictive value (NPV) close to 100% for high-grade squamous intraepithelial lesions (HSILs) and invasive cancers, thereby emphasizing the usefulness of HPV tests in the triage of equivocal or lowgrade cytological smears [10,11]. HPV infection can be detected by many molecular methods, including Hybrid-Capture II assay (HC2; Qiagen, Gaithersburg, MD, USA) and variable HPV genotyping tests, although these methods have different sensitivities and specificities. HC2 detects 13 types of HR-HPV by means of an RNA cocktail probe and provides pooled data about HR-HPV infection, but does not indicate individual HPV types; further, it is the most widely used screening test with proven clinical performance [12-14]. However, because a few HPV types, including HPV 16 and 18 among the many types of HPV, are responsible for most HPV-related cancers, a clinical necessity for HPV genotyping that can distinguish individual types has arisen. Genotyping for specific oncogenic HPV types has also been shown to improve the positive predictive value (PPV) and specificity in predicting HSIL and carcinoma in women with atypical squamous cells of undetermined significance (ASCUS) and low-grade cervical squamous intraepithelial lesions (LSIL) [15]. In addition, in vaccinated women, type-specific HPV testing can be useful to assess the prevalence of specific HPV types, including HPV types that do not have vaccines available [15]. Reflecting this trend, the recently introduced Cobas HPV test (Roche Molecular Systems Inc., Branchburg, NJ, USA) provides specific genotyping data about HPV 16 and 18 in conjunction with pooled HR-HPV results [16]. In Korea, several HPV genotyping tests that use polymerase chain reaction (PCR)-based microarray methods are commercially available, but they lack standardization compared to HC2 and show variable clinical efficacy. We therefore selected two widely used DNA chips, the HPV 9G DNA Chip (9G; Diatech Korea Co. Ltd., Seoul, Korea) and PANArray HPV Genotyping Chip (PANArray; Panagene, Daejeon, Korea), and compared their results with the results from HC2, cytological diagnoses, and histological diagnoses in terms of clinical efficacy. Additionally, genotyping results of these two chips were further validated by direct sequencing.

Giant cell hepatitis (GCH) with autoimmune hemolytic anemia (AHA) is a very rare disease characterized by early onset and severe clinical manifestations, including immune hemolytic anemia and hepatitis with cholestasis. The prognosis is poor despite aggressive immunosuppressive therapy. We report here the first case of GCH with AHA in East Asia. A 2-month-old boy was admitted with jaundice. Blood test indicated abnormal liver function and low hemoglobin. Direct Coombs test and several autoantibodies associated with liver disease were positive, and liver biopsy was consistent with GCH. He was treated with prednisolone and ursodeoxycholic acid, and at the time of writing was in clinical and biochemical remission after prednisolone was stopped.

Gangliocytic paraganglioma is a rare tumor that occurs most commonly in the second portion of the duodenum. It is characterized by its triphasic cellular differentiation: epithelioid neuroendocrine cells, spindle cells with Schwann cell differentiation, and ganglion cells. Most gangliocytic paragangliomas are considered benign and are amenable to local excision. However, to our knowledge, 23 cases with lymph node metastasis have been reported, 1 case of bone metastasis, and 2 cases of liver metastases. Predictive factors that have been suggested for lymph node metastasis include size (larger than 2 cm), young age, and tumors exceeding the submucosal layer. Our objective was to review the clinical features, the histopathologic characteristics, and the differential diagnosis of gangliocytic paraganglioma and to discuss the value of the predictive factors for lymph node metastasis.

Introduction: Periorbital metastasis of colorectal cancer is rare. Therefore, herein, we report a patient with rectal cancer who presented with periorbital metastasis without any systemic metastasis. Patient concerns: The patient was a 57-year-old man who had a painless nodule on his left eyelid. Diagnosis: The patient presented with loose and frequent stools and was diagnosed with rectal adenocarcinoma via colonoscopic biopsy at the local clinic. Curative resection (low anterior resection with temporary ileostomy formation) was performed 4 weeks after completing chemoradiotherapy. The final TNM stage was yp stage T2N0M0. Eight months after the diagnosis of rectal cancer, a protruding lesion was noticed on the patient's left eyelid. Histologic evaluation of the nodule revealed metastatic adenocarcinoma of rectal cancer. Interventions: The patient received neoadjuvant chemoradiotherapy and curative resection for rectal cancer. After excision of the periorbital nodule, he received 5 cycles of chemotherapy. Outcomes: The patient underwent regular follow-up because he was not able to endure chemotherapy; no recurrence has been observed 21 months after the diagnosis of rectal cancer. Histologic examination revealed metastatic adenocarcinoma of rectal cancer on the patient's left eyelid. However, consecutive imaging studies revealed no other metastatic lesions. Finally, the patient was diagnosed with a solitary periorbital metastasis of rectal cancer. Conclusion: This case report helps in understanding the course of progression from rectal cancer to periorbital metastasis.

Mucin 1, cell surface associated (MUC1) is a tumor-associated glycoprotein that has been reported to have an important role in lymphatic invasion and metastasis. The present study aimed to investigate the significance of MUC1 expression in endoscopic biopsy specimens of submucosal invasive gastric carcinomas and the association with lymph node metastasis. The clinicopathological features of 144 cases of surgically resected submucosal invasive gastric carcinomas and their paired endoscopic biopsy specimens were reviewed. Immunohistochemical staining for MUC1 was performed for the 144 endoscopic biopsy specimens. Positive MUC1 expression was identified in 70 (49%) cases. In addition, univariate analysis revealed that MUC1 expression was significantly associated with the presence of poorly-differentiated (P=0.001) and poorly-cohesive (P=0.015) carcinoma cells, undifferentiated type by Japanese classification (P

Background and Aims Endoscopic submucosal dissection (ESD) is now commonly performed as a treatment for colorectal tumors. However, little is known about the relationship between submucosal fibrosis and the outcome of the colonic ESD procedure. The aims of this study were to investigate the relationship between the degree of submucosal fibrosis in colorectal tumors and the outcomes of ESD for these tumors and to evaluate the risk factors for submucosal fibrosis. Methods We retrospectively reviewed the records of patients with colorectal adenoma or carcinoma who had undergone an ESD, during a four-year period from January 2010 to December 2013. The resected specimens were histologically examined after Masson's trichrome staining, and the severity of the submucosal fibrosis was classified as no fibrosis (F0), mild fibrosis (F1), or severe fibrosis (F2). Results Among a total of 173 cases (106 male, mean age 65.0 ± 10.2 years; F0 33, F1 78, F2 62) enrolled, 46 incidences of complications (perforation 19, post-coagulation syndrome 21, bleeding 6) had developed. Multivariate analysis revealed that F2 fibrosis was significantly associated with the development of complications. Submucosal invasion and large tumor size (≥ 30 mm) were identified as independent predictors of F2 fibrosis. Conclusion Severe fibrosis is the most powerful risk factor for complications and can interfere with en bloc resections. The possibility of submucosal fibrosis should be considered, and the procedure should be cautiously performed in cases where the tumor diameter is greater than 30 mm and when submucosal cancer is suspected.

Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer. Graphical Abstract Keywords: Prostatic Neoplasms, PPAR gamma, Immunohistochemistry, Real-Time Polymerase Chain Reaction INTRODUCTION Prostate cancer is the second most frequently diagnosed cancer affecting male adults and the sixth most common cause of cancer associated death in men across the world (1). The major risk factors for prostate cancer are old age, race, inherited susceptibility and environmental and behavioral factors such as diets (2, 3). Treatment options of prostate cancer include active surveillance, surgical resection, androgen ablation therapy, radiotherapy, and cryotherapy variously depending on risk grouping, medical comorbidities and age at the diagnosis of the patients (4, 5, 6). Prostate cancer is heterogeneous in terms of clinical behaviors, histological and molecular features, and treatment options (4, 5, 6, 7). Although most patients with low and intermediate-risk prostate cancer follow an indolent clinical course and are potentially curative by surgical resection or radiotherapy, patients with high-risk prostate cancer have higher rate of cancer related death and conventional chemotherapy and radiation therapy are of limited effectiveness for them (2, 4, 5, 6, 8). Androgen deprivation therapy has good efficacy for advanced disease to lead to either a partial or complete remission initially. However most patients evolve towards an androgen-independent state within a few years and result in death due to widespread metastasis (6). Therefore, more improved treatments and novel biomarkers are strongly needed in order to overcome metastasis and lethal recurrence for advanced prostate cancer as well as unpredictable cases of low or intermediate risk groups. Peroxisome proliferator-activated receptors (PPARs) are a group of 50-kDa ligand-dependent transcription factors localized at human chromosome 3p25 and belong to a member of the nuclear hormone receptor superfamily such as steroid and thyroid hormones (9, 10, 11). They are composed of three isoforms (PPAR-α, PPAR-γ, and PPAR-δ/β) and require heterodimerization with the retinoid X receptor for optimal DNA binding to specific response elements, termed to as peroxisome proliferator response elements (PPREs), in the promoter of the various target genes (9, 10, 11). The nuclear receptor superfamily was named because they show prominent nuclear localization. Among the subtypes, PPAR-γ is known to play a prominent role in adipocyte differentiation, the inflammatory response and peripheral glucose utilization (9, 11). Recent studies have suggested that PPAR-γ play a key role in tumorigenesis as a tumor suppressor and PPAR-γ agonists showed antiproliferative and proapoptotic actions in cancers (8, 12, 13). Currently PPAR-γ agonists including the most active natural ligand, 15-deoxy-D-12, 14-prostaglandin J2 (15-dPGJ2) and the most specific PPAR-γ synthetic agonists, the thiazolidinediones (TZDs) are used for enhancing insulin sensitivity in type II diabetes patients (9). And they have been introduced in clinical trials for treatment of several malignancies such as colorectal and esophageal cancers (9, 14). Many in vivo or in vitro studies have shown antineoplastic effect of PPAR-γ ligands in prostate cancers (15, 16). It has been reported that exposure to the TZDs has been shown to increase apoptotic activity in LNCaP, C4-2, and PC-3 prostate cancer cells and a combination therapy using histone deacetylases inhibitors and PPAR-γ agonists decrease invasiveness of the prostate adenocarcinoma cells in vivo (13, 15, 16). Efatutazone is recently introduced as a novel third-generation TZD PPAR-γ agonist, which is at least 500-fold more potent than the other TZDs such as troglitazone and pioglitazone (17). Therefore, PPAR-γ and its agonists have recently drawn more attention and promise in terms of chemoprevention and chemotherapy for cancer treatment and it has been also considered as a promising molecular target for anticancer targeted therapy development in prostate cancers (18). However, there is little or controversial information on PPAR-γ expression and clinical implications in the clinical specimen of prostate cancers (18, 19, 20). Whereas Nakamura et al. (19) reported PPAR-γ expression showed an inverse correlation with worse clinical parameters including pT stage and serum PSA levels, Rogenhofer et al. (20) reported PPAR-γ protein and mRNA expression were found to be significantly higher in advanced prostate cancers than in localized cancer. Therefore, further studies are needed to obtain a better understanding of the clinical roles of PPAR-γ in human prostate cancers for considering a potential trial of PPAR-γ ligands therapy for the patients. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues of a clinically well-characterized prostatectomy cohort by immunohistochemistry and quantitative real-time PCR in a Korean population.

Purpose In 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype. Materials and Methods A total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped. Results In univariate survival analysis, tumor grade (p < 0.0001), extent (p < 0.0001), size (p < 0.0001), lymph node metastasis (p=0.0063), and L-cell phenotype (p < 0.0001) showed significant correlation with the prognosis of rectal NENs; however, none of these markers achieved independent significance in multivariate analysis. The 10-year OS of tumors of NET grade 1, < 10 mm, the mucosa/submucosa was 97.58%, 99.47%, and 99.03%, respectively. L-Cell marker, glucagon II (GLP-1&2), with a cut off score of > 10, is useful in defining L-Cell type. In this study, an L-cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa. Conclusion From these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters.

The possibility of lymph node metastasis is critical to the assessment of the indication for endoscopic submucosal dissection. The differentiation of tumors is an important predicting factor for lymph node metastasis. Even though gastric cancers frequently show intratumoral heterogeneity, most studies have not considered the effects of the minor histologic components. The purpose of this study was to investigate the relationship between the presence of undifferentiated type histology (UD-min) within differentiated type tumors and lymph node metastases in early gastric cancer confined to the mucosal layer.A retrospective study of 847 patients who underwent surgery for differentiated early gastric cancer, confined to mucosa, was conducted. We analyzed the proportion of the undifferentiated type components of the tumor and their relationship with lymph node metastasis.The overall rate of lymph node metastasis was 1.7 % (14/847 patients) and 215 differentiated tumors (25.4 %) have UD-min. UD-min was associated with female sex, younger age, larger tumor size, and the presence of ulcer. Lymph node metastasis rate with or without UD-min was 5.1 % (11/215) versus 0.5 % (3/632), respectively (p0.001). UD-min was found to be associated with lymph node metastasis in the multivariate analyses (odds ratio [OR] = 4.39, CI 1.08-17.89). When three risk factors (tumor size2 cm, ulcer, and UD-min) were present concurrently, the rate of lymph node metastasis was high (10 %).The presence of an UD-min component should be considered when assessing curative resection status of endoscopic submucosal dissection for differentiated type mucosal cancer.