Development of quality assurance program for digital pathology by the Korean Society of Pathologists.

BACKGROUND: Digital pathology (DP) using whole slide imaging is a recently emerging game changer technology that can fundamentally change the way of working in pathology. The Digital Pathology Study Group (DPSG) of the Korean Society of Pathologists (KSP) published a consensus report on the recommendations for pathologic practice using DP. Accordingly, the need for the development and implementation of a quality assurance program (QAP) for DP has been raised. METHODS: To provide a standard baseline reference for internal and external QAP for DP, the members of the Committee of Quality Assurance of the KSP developed a checklist for the Redbook and a QAP trial for DP based on the prior DPSG consensus report. Four leading institutes participated in the QAP trial in the first year, and we gathered feedback from these institutes afterwards. RESULTS: The newly developed checklists of QAP for DP contain 39 items (216 score): eight items for quality control of DP systems; three for DP personnel; nine for hardware and software requirements for DP systems; 15 for validation, operation, and management of DP systems; and four for data security and personal information protection. Most participants in the QAP trial replied that continuous education on unfamiliar terminology and more practical experience is demanding. CONCLUSIONS: The QAP for DP is essential for the safe implementation of DP in pathologic practice. Each laboratory should prepare an institutional QAP according to this checklist, and consecutive revision of the checklist with feedback from the QAP trial for DP needs to follow.

Overexpression of FRAT1 protein is closely related to triple-negative breast cancer.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis and a lack of targeted therapy. Overexpression of FRAT1 is thought to be associated with this aggressive subtype of cancer. Here, we performed a comprehensive analysis and assessed the association between overexpression of FRAT1 and TNBC. Methods: First, using different web-based bioinformatics platforms (TIMER 2.0, UALCAN, and GEPIA 2), the expression of FRAT1 was assessed. Then, the expression of the FRAT1 protein and hormone receptors and HER2 status were assessed by immunohistochemical analysis. For samples of tumors with equivocal immunoreactivity, we performed silver in situ hybridization of the HER2 gene to determine an accurate HER2 status. Next, we used the R package and bc-GenExMiner 4.8 to analyze the relationship between FRAT1 expression and clinicopathological parameters in breast cancer patients. Finally, we determined the relationship between FRAT1 overexpression and prognosis in patients. Results: The expression of FRAT1 in breast cancer tissues is significantly higher than in normal tissue. FRAT1 expression was significantly related to worse overall survival (P < 0.05) and was correlated with these clinicopathological features: T stage, N stage, age, high histologic grade, estrogen receptor status, progesterone receptor status, Her-2 status, TNBC status, basal-like status, CK5/6 status, and Ki67 status. Conclusion: FRAT1 was overexpressed in breast cancer compared to normal tissue, and it may be involved in the progression of breast cancer malignancy. This study provides suggestive evidence of the prognostic role of FRAT1 in breast cancer and the therapeutic target for TNBC.

Fatty acid synthetase expression in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has a relatively poor prognosis. Research has identified potential metabolic targets, including fatty acid metabolism, in TNBC. The absence of effective target therapies for TNBC led to exploration of the role of fatty acid synthetase (FASN) as a potential target for TNBC therapy. Here, we analyzed the expression of FASN, a representative lipid metabolism-related protein, and investigated the association between FASN expression and Ki-67 and the programmed death ligand 1 (PD-L1) biomarkers in TNBC. METHODS: Immunohistochemical expression of FASN was analyzed in 166 patients with TNBC. For analytical purposes, patients with 0-1+ FASN staining were grouped as low-grade FASN and patients with 2-3+ FASN staining as high-grade FASN. RESULTS: FASN expression was observed in 47.1% of TNBC patients. Low and high expression of FASN was identified in 75.9% and 24.1%, respectively, and no statistically significant difference was found in T category, N category, American Joint Committee on Cancer stage, or recurrence rate between the low and high-FASN expression groups. Ki-67 proliferation level was significantly different between the low and high-FASN expression groups. FASN expression was significantly related to Ki-67 as the level increased. There was no significant difference in PD-L1 positivity between the low- and high-FASN expression groups. CONCLUSIONS: We identified FASN expression in 166 TNBC patients. The Ki-67 proliferation index was positively correlated with FASN level, indicating higher proliferation activity as FASN increases. However, there was no statistical association with PD-L1 SP142, the currently FDA-approved assay, or FASN expression level.

Standardization of the pathologic diagnosis of appendiceal mucinous neoplasms.

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the "Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm" to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

High Concordance of Genomic Profiles between Primary and Metastatic Colorectal Cancer.

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.

Histology and its prognostic effect on KRAS-mutated colorectal carcinomas in Korea.

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.

Concordance of Programmed Death-Ligand 1 Expression between SP142 and 22C3/SP263 Assays in Triple-Negative Breast Cancer.

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.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

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.

Case report of periorbital metastasis from rectal cancer.

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.

Standardized Pathology Report for Colorectal Cancer, 2nd Edition.

The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.

Cross-national analysis about the difference of histopathological management in Tis and T1 colorectal cancer between Japan and Korea.

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.

Assessing significant fibrosis using imaging-based elastography in chronic hepatitis B patients: Pilot study.

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.

Comprehensive analysis for diagnosis of preoperative non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

OBJECTIVE: The 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. METHODS: We 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. RESULTS: K-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. CONCLUSION: The 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.

Correlations of the Gastric and Duodenal Microbiota with Histological, Endoscopic, and Symptomatic Gastritis.

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⁻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⁻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.

Centrosome Linker-induced Tetraploid Segregation Errors Link Rhabdoid Phenotypes and Lethal Colorectal Cancers.

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.

[Identification of Nodular Gastritis among Patients Diagnosed with Lymphofollicular Gastritis on a Gastric Biopsied Specimen].

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.

The histologic detection of Helicobacter pylori in seropositive subjects is affected by pathology and secretory ability of the stomach.

BACKGROUND: Helicobacter pylori is unevenly distributed in hypochlorhydric environments. The study aim was to elucidate the risk factors for a negative Giemsa staining finding in seropositive subjects by measuring the secretory ability of the stomach. METHODS: Subjects aged over 18 years were included consecutively after endoscopic biopsy at gastric lesions with color or structural changes. Blood was sampled for the serum pepsinogen (PG) assay and H. pylori serology test. After excluding the subjects with past H. pylori eradication, the risk factors for a negative Giemsa staining finding in seropositive subjects were analyzed. RESULTS: Among 872 included subjects, a discrepancy between the serum anti-H. pylori IgG and Giemsa staining findings was found in 158 (18.1%) subjects, including 145 Giemsa-negative, seropositive subjects. Gastric adenocarcinoma/adenoma (OR = 11.090, 95% CI = 3.490-35.236) and low serum PG II level (OR = 0.931, 95% CI = 0.899-0.963) were the independent risk factors for a negative Giemsa staining finding in seropositive subjects. The cutoff value of serum PG II level was 7.45 ng/mL (area under curve [AUC] = 0.904, 95% CI = 0.881-0.927). Follow-up studies of Giemsa staining at different sites of the stomach revealed that 75% of the Giemsa-negative seropositive subjects with adenocarcinoma are positive, whereas none of those with low serum PG II level of <7.45 ng/mL revealed positive findings. CONCLUSIONS: The risk of a negative Giemsa staining finding in seropositive subjects is increased in gastric adenocarcinoma/adenoma specimens and in subjects with a diminished gastric secretory ability with low serum PG II level of <7.45 ng/mL. A false-negative Giemsa staining finding is common in subjects with adenocarcinoma, and therefore, additional biopsies at different sites should be performed in these subjects.

External Validation of a Gastric Cancer Nomogram Derived from a Large-volume Center Using Dataset from a Medium-volume Center.

PURPOSE: Recently, a nomogram predicting overall survival after gastric resection was developed and externally validated in Korea and Japan. However, this gastric cancer nomogram is derived from large-volume centers, and the applicability of the nomogram in smaller centers must be proven. The purpose of this study is to externally validate the gastric cancer nomogram using a dataset from a medium-volume center in Korea. MATERIALS AND METHODS: We retrospectively analyzed 610 patients who underwent radical gastrectomy for gastric cancer from August 1, 2005 to December 31, 2011. Age, sex, number of metastatic lymph nodes (LNs), number of examined LNs, depth of invasion, and location of the tumor were investigated as variables for validation of the nomogram. Both discrimination and calibration of the nomogram were evaluated. RESULTS: The discrimination was evaluated using Harrell's C-index. The Harrell's C-index was 0.83 and the discrimination of the gastric cancer nomogram was appropriate. Regarding calibration, the 95% confidence interval of predicted survival appeared to be on the ideal reference line except in the poorest survival group. However, we observed a tendency for actual survival to be constantly higher than predicted survival in this cohort. CONCLUSIONS: Although the discrimination power was good, actual survival was slightly higher than that predicted by the nomogram. This phenomenon might be explained by elongated life span in the recent patient cohort due to advances in adjuvant chemotherapy and improved nutritional status. Future gastric cancer nomograms should consider elongated life span with the passage of time.

Diagnostic Limitation of Fine-Needle Aspiration (FNA) on Indeterminate Thyroid Nodules Can Be Partially Overcome by Preoperative Molecular Analysis: Assessment of RET/PTC1 Rearrangement in BRAF and RAS Wild-Type Routine Air-Dried FNA Specimens.

Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the RET/PTC1 rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of RET/PTC1 rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. RET/PTC1 rearrangements of 76 resected BRAF and RAS wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of RET/PTC1 rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of RET/PTC1 rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 BRAF and RAS wild-type classical PTCs had RET/PTC1 rearrangement. Comparison of RET/PTC1 rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 (p = 0.002). The RET/PTC1 rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the BRAF and RAS wild-type PTCs harbored RET/PTC1 rearrangements.

Molecular Profiling of Papillary Thyroid Carcinoma in Korea with a High Prevalence of BRAFV600E Mutation.

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 ALK rearrangements (5.6%, 2.1%, 0.4%, and 0%, respectively). The low prevalence of NTRK1 fusions and the absence of an ALK fusion detected in Korea may also be attributed to the higher prevalence of the BRAFV600E mutation. There were significant differences in the frequency of the genetic alterations among the histologic variants of PTC. The prevalence of NIFTP in PTC was 2.7%, and among the NIFTPs, 28.6% and 57.1% harbored BRAF and RAS mutations, respectively. Clinicopathologic factors and mutational profiles between NIFTP and encapsulated follicular variant PTC with capsular invasion group were not significantly different. CONCLUSIONS: Genetic alterations in PTC vary among its different histologic variants and seem to be different in each ethnic group.