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Background: Papillary breast lesions (PBLs) comprise diverse entities from benign and atypical lesions to malignant tumors. Although PBLs are characterized by a papillary growth pattern, it is challenging to achieve high diagnostic accuracy and reproducibility. Thus, we investigated the diagnostic reproducibility of PBLs in core needle biopsy (CNB) specimens with World Health Organization (WHO) classification.Methods: Diagnostic reproducibility was assessed using interobserver variability (kappa value, κ) and agreement rate in the pathologic diagnosis of 60 PBL cases on CNB among 20 breast pathologists affiliated with 20 medical institutions in Korea. This analysis was performed using hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin 5 (CK5) and p63. The pathologic diagnosis of PBLs was based on WHO classification, which was used to establish simple classifications (4-tier, 3-tier, and 2-tier). Results: On WHO classification, H&E staining exhibited ‘fair agreement’ (κ = 0.21) with a 47.0% agreement rate. Simple classifications presented improvement in interobserver variability and agreement rate. IHC staining increased the kappa value and agreement rate in all the classifications. Despite IHC staining, the encapsulated/solid papillary carcinoma (EPC/SPC) subgroup (κ = 0.16) exhibited lower agreement compared to the non-EPC/SPC subgroup (κ = 0.35) with WHO classification, which was similar to the results of any other classification systems. Conclusions: Although the use of IHC staining for CK5 and p63 increased the diagnostic agreement of PBLs in CNB specimens, WHO classification exhibited a higher discordance rate compared to any other classifications. Therefore, this result warrants further intensive consensus studies to improve the diagnostic reproducibility of PBLs with WHO classification.

This study was performed to compare endoscopic mucosal resection (EMR) with hot snare polypectomy (HSP) in terms of the complete resection rate and the incidence of adverse events for resecting small (5–10 mm) colorectal polyps. Small colorectal polyps (5–10 mm) with neoplastic features were randomly allocated to either the HSP or EMR group. A submucosal injection was performed prior to hot snaring in the EMR group only. Complete resection was defined as the absence of neoplastic tissue from two additional biopsies of the polypectomy site. R0 resection was defined as the absence of neoplastic tissue at the margin of the resected specimen. A total of 362 colon polyps from 272 patients were included, and 167 polyps in the HSP group and 155 polyps in the EMR group were analyzed. Between the polypectomy techniques, there was no significant difference in the complete resection rates, which were 96.4% (161/167) in the HSP group and 95.5% (148/155) in the EMR group (P = 0.67). The R0 resection rate in the HSP and EMR groups was significantly different, with 49.7% (83/167) and 74.8% (116/155), respectively (P

The diagnosis of small intestinal adenocarcinoma (SIAC) is usually determined at an advanced stage due to non-specific symptoms and the difficulty of exploring the small intestine. Therefore, the majority of SIAC patients have limited chemotherapeutic options. Until recently, the development of novel and effective therapies for SIAC have been limited owing to the low number of samples that have been collected and the low incidence of SIAC. Immunotherapies are becoming a focus. However, in SIAC, only a few studies to identify immunotherapy-responsive subgroups and their prognostic indicators have been reported. In the present study, we categorise primary SIAC into four types of tumour immune microenvironments and propose a strategy for identifying patient subgroups that are most likely to be immunotherapy-responsive. Formalin-fixed, paraffin-embedded tissue samples of a multicentre cohort of patients with SIAC (n=195) were collected using tissue microarrays. Immunohistochemical (IHC) stains for PD-L1, PD-1, and CD8 were performed, and microsatellite instability was evaluated using an IHC stain. Tumour microenvironment immune type (TMIT) I [PD-L1-positive tumour cells and CD8-high tumour-infiltrating lymphocytes (TILs)] and TMIT III (PD-L1-positive tumour cells and CD8-low TILs) show the best and worse prognoses, respectively. PD-L1 expression was significantly associated with high microsatellite instability (MSI) status. CD8-high TILs were positively correlated with PD-1-high TILs and high MSI. The TMIT I subgroup demonstrated a more patent CD8/PD-L1/PD-1 signalling pathway compared to other TMITs. Therefore, the TMIT I subgroup can be expected to have an effective response to immune checkpoint inhibitor therapies in SIAC. Such classification of SIACs into four immune types can be useful in predicting the prognosis of patients and the identification of immunotherapy-responsive subgroups.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p &lt, 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p &lt, 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Context.— The roles of the gallbladder and cystic duct (CD) invasions in distal bile duct carcinoma (DBDC) have not been well elucidated. Objective.— To define the characteristics and prognostic significance of gallbladder or CD invasions in patients with DBDC. Design.— Organ invasion patterns with clinicopathologic features were assessed in 258 resected DBDCs. Results.— CD invasions (N = 31) were associated with frequent concomitant pancreatic and/or duodenal invasions (23 of 31, 74%) and showed stromal infiltration (16 of 31, 52%) and intraductal cancerization (15 of 31, 48%) patterns. In only 2 cases, invasions with intraductal cancerization were observed in the gallbladder neck. Conversely, all pancreatic (N = 175) and duodenal (83) invasions developed through stromal infiltration. CD invasions were associated with larger tumor size (P = .001), bile duct margin positivity (P = .001), perineural invasions (P = .04), and higher N categories (P = .007). Patients with pancreatic or duodenal invasions had significantly lower survival rates than those without pancreatic (median, 31.0 versus 93.9 months) or duodenal (27.5 versus 56.8 months, P < .001, both) invasions. However, those with gallbladder or CD invasions did not have different survival times (P = .13). Patients with concomitant gallbladder/CD and pancreatic/duodenal invasions demonstrated significantly lower survival rates than those without organ invasions (P < .001). Conclusions.— Gallbladder invasions were rare in DBDCs as neck invasions with intraductal cancerization. CD invasions occurred by stromal infiltrations and intraductal cancerization, whereas all pancreatic and duodenal invasions had stromal infiltration patterns. Gallbladder and/or CD invasions did not affect survival rates of patients with DBDC, while pancreatic and duodenal invasions affected survival rates. Therefore, these differences in survival rates may originate from the different invasive patterns of DBDCs.

Purpose To investigate the correlation of the strain elasticity of breast cancer with histologic features, immunohistochemical markers and molecular subtypes that are known to be factors related to prognosis. Materials and Methods B-mode ultrasound and strain elastography were performed in 123 patients (mean age, 53.4; range, 28–82) with invasive ductal carcinoma (IDC) (mean size, 1.54 cm; range, 0.4–7.0 cm). Histologic grade, lymph node (LN) status, lymphovascular invasion, immunohistochemical biomarkers [estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), CK5/6, epidermal growth factor receptor, and Ki-67] and molecular subtypes were determined from surgical pathology reports. The relationships between these factors and elasticity scores were evaluated. Results LN involvement was associated with a higher elasticity score which was statistically significant (p = 0.042). The tumor size, lymphovascular invasion, histologic grades, immunohistochemical markers and molecular subtypes had no significant correlation with the elasticity score (p > 0.05 for all). However, the IDCs with larger size and a positive lymphovascular invasion tended to have higher elasticity scores. Furthermore, higher histologic grade cancers and the HER2 overexpression-type tended to have lower elasticity scores. Conclusion The elasticity score of IDC had a significant correlation with LN involvement but no statistically significant correlation with the histologic features, immunohistochemical markers or molecular subtypes.

Background and Aims Cold snare polypectomy (CSP) and jumbo forceps polypectomy (JFP) have been shown to be effective for removing diminutive colorectal polyps (DCPs) (≤5 mm). However, no study has compared complete resection rates between CSP and JFP for DCPs. The aim of this study was to compare the efficacy and safety of JFP with CSP for the removal of DCPs. Methods This was a prospective randomized controlled trial from 2 tertiary-care referral centers. A total of 1003 patients were screened, and 169 patients with 196 DCPs were enrolled. The main outcome was complete polyp resection rate. Results Of 196 diminutive polyps, 177 (90.3%) were adenomatous polyps. The overall complete resection rate was 92.1% (163/177). The complete resection rate was not significantly different between JFP and CSP groups (92.0% vs 92.2%; P = .947). JFP achieved complete resection rates comparable with CSP for polyps >3 mm (90.3% vs 89.8%; P = .928). Polypectomy procedure time, tissue retrieval rate, and rate of postpolypectomy adverse events were not significantly different between the 2 groups. Conclusions Both JFP and CSP achieved complete resection rates of >90% for DCPs. Thus, JFP may be considered for polypectomy of DCPs. (International clinical trial registry number: KCT0002805.)

BackgroundGallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.Materials and MethodsTo determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.ResultsThree of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.ConclusionMMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

Background: Endoscopic ultrasound-guided ablation (EUS-A) therapy is a minimally invasive procedure for pancreatic-cystic tumors in patients with preoperative comorbidities or in patients who are not indicated for surgical resection. However, histopathologic characteristics of pancreatic cysts after ablation have not been well-elucidated. Methods: Here, we analyzed pathological findings of 12 surgically resected pancreatic cysts after EUS-A with ethanol and/or paclitaxel injection. Results: Mean patient age was 49.8 ± 13.6 years with a 0.3 male/female ratio. Clinical impression before EUS-A was predominantly mucinous cystic neoplasms. Mean cyst size before and after ablation therapy was similar (3.7 ± 1.0 cm vs. 3.4 ± 1.6 cm; p = 0.139). Median duration from EUS-A to surgical resection was 18 (range, 1–59) months. Mean percentage of the residual neoplastic lining epithelial cells were 23.1 ± 37.0%. Of the resected cysts, 8 cases (67%) showed no/minimal (Conclusion: Above all, diffuse egg shell-like calcification along the pancreatic cystic walls with residual lining epithelia and/or ovarian-type stroma were characteristics of pancreatic cysts after EUS-A. Therefore, understanding these histologic features will be helpful for precise pathological diagnosis of pancreatic cystic tumor after EUS-A, even without knowing the patient’s history of EUS-A.

The tumor microenvironment (TME) has become an important area of investigation with respect to improving prognosis in malignancies. Here we evaluated TME prognostic risk in small intestinal adenocarcinomas based on histologic assessment of tumor budding at the peritumoral-invasive front (pTB) and stromal tumor-infiltrating lymphocytes (sTILs). pTB and sTILs were analyzed in 230 surgically resected small intestinal adenocarcinomas, as recommended by the International Tumor Budding Consensus Conference (ITBCC) and the International TILs Working Group (ITWG). On the basis of high levels of pTB count (≥10) and sTIL density (≥20%), we combined pTB and sTIL to produce a collective TME-based prognostic risk index: low-risk (pTBLow/sTILHigh; n=39, 17.0%), intermediate-risk (pTBLow/sTILLow or pTBHigh/sTILHigh; n=99, 43.0%), and high-risk groups (pTBHigh/sTILLow; n=92, 40.0%). TME risk index provided better prognostic stratification than the individual pTB and sTIL (14.9 vs. 6.7 vs. 10.3). Tumors with higher TME prognostic risk were associated with an infiltrative growth pattern and nonintestinal immunophenotype (both P=0.001), pancreatic invasion (P=0.010), lymphovascular (P

Objective: Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to KRAS mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well understood. Materials and Methods: To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and KRAS genotype, in 185 small intestinal adenocarcinomas. Results: The loss of HES-1 expression (HES-1Loss) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (P = 0.018), pancreatic invasion (P = 0.005), high grade (P =0.043), and non-tubular histology (P = 0.004). Specifically, in tumors with mutant KRAS (KRASMT), HES-1Loss was related to proximal location (P = 0.024), high T and N categories (P = 0.005 and P = 0.047, respectively), and pancreatic invasion (P = 0.004). Patients with HES-1Loss showed worse overall survival compared to those with intact HES-1 (HES-1Intact) (P = 0.013). Patients with HES-1Loss/KRASMT (median, 17.3 months) had significantly worse outcomes than those with HES-1Intact/KRASWT (39.9 months), HES-1Intact/KRASMT (47.6 month), and HES-1Loss/KRASWT (36.2 months) (P = 0.010). By multivariate analysis, HES-1Loss (hazard ratio = 1.55, 95% confidence interval (CI), 1.07 – 2.26; P = 0.022) remained an independent prognostic factor. Conclusion: HES-1 expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters &le, 4 tumor cells) and PDC (clusters &ge, 5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (&le, 4), grade-2 (5&ndash, 9), or grade-3 (&ge, 10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months, p = 0.007) in the lower stage (stages I&ndash, II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

Purpose T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N category adopted a 3-tier classification system based on the number of metastatic nodes. Materials and Methods To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions. Results T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T category could discriminate patient survival by both pairwise (T1 and T2, p=0.011; T2 and T3, p < 0.001) and overall (p < 0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p < 0.001; N1 and N2, p=0.579) and overall (p < 0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002; II and III, p=0.015) and overall (p < 0.001) comparisons. On multivariate analyses, T and N categories (p=0.014 and p=0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors. Conclusion The T andNcategories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis.

The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2−) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRAS(MT)) (11.1 months) had significantly shorter overall survival than those with SOX2−/KRAS(WT) (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.

Heme oxygenase-1 (HO-1), a stress-response protein, is highly induced in various carcinomas. It is implicated in carcinogenesis and tumor progression. High HO-1 expression is associated with better prognosis of patients with colorectal and gastric cancers. Induction or inhibition of HO-1 can mediate chemo-sensitivity, therefore it might be a therapeutic target to develop anticancer agents. To define the clinicopathological and prognostic significance of HO-1 expression in small-intestinal adenocarcinomas (SIACs), immunohistochemical microarray analysis of HO-1 expression was performed for 191 surgically resected SIAC cases and results were compared with various clinicopathologic variables, including survival. HO-1 was highly expressed in 127 (66.5%) cases. Patients with high HO-1 expression were associated with younger age (P = 0.048), lower pT category (P = 0.017), and less pancreatic invasion (P = 0.047). Patients with high HO-1 expression tended to have longer overall survival (median, 38.5 months) than those with low HO-1 expression (24.5 months), although the difference in overall survival was not statistically significant (P = 0.677). In summary, high HO-1 expression is frequently observed in SIACs. It is related to favorable clinicopathologic parameters, including younger age, lower T category, and less pancreatic invasion. Therefore, HO-1 may serve as a prognostic marker and a new target to modulate chemotherapeutic effects in patients with SIACs.

This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2′3′-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC). Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39 months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (P = 0.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (P = 0.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS. CD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated.

Background Histologic grade is the most important predictor of the clinical outcome of non-muscle invasive (Ta, T1) papillary urothelial carcinoma (NMIPUCa), but its ambiguous criteria diminish its power to predict recurrence/progression for individual patients. We attempted to find an objective and reproducible histologic predictor of NMIPUCa that correlates well with the clinical outcome. Methods A total of 296 PUCas were collected from the Departments of Surgical Pathology of 11 institutions in South Korea. The clinical outcome was grouped into no event (NE), recurrence (R), and progression (P) categories. All 25 histological parameters were numerically redefined. The clinical pathology of each case was reviewed individually by 11 pathologists from 11 institutions based on the 2004 WHO criteria and afterwards blindly evaluated by two participants, based on our proposed parameters. Univariate and multivariate logistic regression analyses were performed using the R software package. Results The level of mitoses was the most reliable parameter for predicting the clinical outcome. We propose a four-tiered grading system based on mitotic count (> 10/10 high-power fields), nuclear pleomorphism (smallest-to-largest ratio of tumor nuclei >20), presence of divergent histology, and capillary proliferation (> 20 capillary lumina per papillary core). Conclusions The level of mitoses at the initial bladder biopsy and transurethral resection (TUR) specimen appeared to be an independent predictor of the Ta PUCa outcome. Other parameters include the number of mitoses, nuclear pleomorphism, divergent histology, and capillary proliferation within the fibrovascular core. These findings may improve selection of patients for a therapeutic strategy as compared to previous grading systems. Electronic supplementary material The online version of this article (doi:10.1186/s13000-017-0639-y) contains supplementary material, which is available to authorized users.

// Sun-Young Jun 1 , Eui-Jin Lee 2 , Mi-Ju Kim 3 , Sung Min Chun 4 , Young Kyung Bae 5 , Soon Uk Hong 6 , Jene Choi 4 , Joon Mee Kim 7 , Kee-Taek Jang 8 , Jung Yeon Kim 9 , Gwang Il Kim 10 , Soo Jin Jung 11 , Ghilsuk Yoon 12 , Seung-Mo Hong 4 1 Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea 2 Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea 3 Asan Institute for Life Science, Asan Medical Center, Seoul, Korea 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 5 Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea 6 Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea 7 Department of Pathology, Inha University College of Medicine, Incheon, Korea 8 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea 10 Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 11 Department of Pathology, Inje University College of Medicine, Busan, Korea 12 Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea Correspondence to: Seung-Mo Hong, email: smhong28@gmail.com Ghilsuk Yoon, email: gsyoon@knu.ac.kr Keywords: small intestinal adenocarcinoma, Lynch syndrome, hereditary nonpolyposis colorectal cancer syndrome, microsatellite instability, DNA mismatch repair Received: September 09, 2016 Accepted: January 24, 2017 Published: February 11, 2017 ABSTRACT Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P =0.04) and more likely to have mucinous adenocarcinomas ( P= 0.003), and tended to survive longer ( P =0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

The clinicopathological and prognostic significance of olfactomedin-4 (OLFM4) expression has not yet been elucidated in extrahepatic bile duct carcinomas (EBDCs). Immunohistochemical analysis of OLFM4 expression in 31 normal biliary epithelia, 33 biliary intraepithelial neoplasias (BilINs), and 180 surgically resected EBDCs (54 perihilar and 126 distal) was performed and was used to analyze clinicopathological variables including patient survival. The expression of OLFM4 showed a progressive increase from normal biliary epithelia (0.2 ± 0.4) to BilINs (2.8 ± 3.2) to EBDCs (4.6 ± 4.2; P0.001). OLFM4 was highly expressed in 26.1% (47/180) of the EBDC cases, and high OLFM4 levels were more frequently observed in tumors with nodular growth (P = 0.029), well differentiation (P = 0.011), and lower T-category (P = 0.025) and stage grouping (P = 0.013). Patients with EBDC having high expression of OLFM4 had better survival than those with low expression of OLFM4 (median, 43.3 vs. 29.2 months; P = 0.037). OLFM4 might play an important role in carcinogenesis and in the progression from BilINs to EBDCs. High OLFM4 expression predicted less aggressive clinical behavior in patients with EBDC.

Objectives Assessment of tumor-infiltrating lymphocytes (TILs) may predict the prognosis and therapeutic benefit of immunotherapy in small intestinal adenocarcinoma (SIAC) patients. Methods TILs were evaluated in 231 surgically resected SIACs and compared with microsatellite instability (MSI) and clinicopathologic variables. The average number of intraepithelial TILs (iTILs) and the average density of stromal TILs (sTILs) were calculated separately. Results High iTIL count (≥2 per high-power field) was associated with MSI-high, whereas high sTIL density (≥20% on ×200 magnification) was not. High iTIL count and high sTIL density were related to distal tumor location, medullary carcinoma, high Crohn-like lymphoid reaction counts, and fewer pancreatic invasions. SIAC patients with high iTIL count or high sTIL density had better survival than those with low values. On multivariate analysis, MSI, high sTIL density, proximal locations, lower N category, and absence of lymphovascular invasions and retroperitoneal seeding were the best independent prognostic predictors. Conclusions High sTIL density can be used as a prognostic indicator and high iTIL count may provide a basis for the clinical use of targeted immunotherapy in SIAC patients.

Nonductal pancreatic neoplasms, including solid pseudopapillary neoplasms, acinar cell carcinomas, and pancreatoblastomas, are uncommon. These entities share overlapping gross, microscopic, and immunohistochemical features, such as well-demarcated solid neoplasms, monotonous cellular tumor cells with little intervening stroma, and abnormal beta-catenin expression. Each tumor also has unique clinicopathologic characteristics with diverse clinical behavior. To differentiate nonductal pancreatic neoplasms, identification of histologic findings, such as pseudopapillae, acinar cell features, and squamoid corpuscles, is important. Immunostainings for acinar cell or neuroendocrine markers are helpful for differential diagnosis. This article describes the clinicopathologic and immunohistochemical features of nonductal pancreatic cancers.

Several techniques are recommended for the histologic diagnosis of gastric subepithelial tumors (SETs). The purpose of our study was to evaluate the diagnostic yield and safety of endoscopic ultrasonography-guided single-incision needle knife (SINK) biopsy for the diagnosis of gastric SETs. A retrospective review of patients who received biopsy for gastric SETs from August 2012 to May 2015 was conducted. Patients who received endoscopic ultrasonography and were found to have a SET originating from the muscularis propria of the stomach were included in the study. The aim of our study was to investigate the safety and diagnostic yield of SINK biopsy for gastric SETs. A total of 31 patients received SINK biopsy for SETs. The diagnostic yield of SINK biopsy was 87 % (95 % CI 75–100 %), and the diagnostic accuracy was 89 % (95 % CI 74–105 %). The sensitivity of SINK biopsy to identify gastrointestinal stromal tumors was 83 % (95 % CI 52–98 %); the specificity was 100 % (95 % CI 59–100 %); the positive predictive value was 100 % (95 % CI 69–100 %); and the negative predictive value was 78 % (95 % CI 40–97 %). There were no procedure-related adverse events during and after procedure. The use of SINK biopsy technique in patients with SETs is a good diagnostic tool with high diagnostic yield and accuracy. The method is simple, safe, and associated with few complications.

Recently, a high-risk human papillomavirus (HR-HPV) detecting assay alone could be used as a first-line screening tool for cervical cancer, although the test system has been limited to the Cobas 4800 HPV test. However, the screening efficiency of the HPV chip, which is widely used in Eastern Asia because of the high prevalence of non16/18 HR-HPV genotypes, has not been well elucidated. After selecting 300 women who were co-tested using the PANArray HPV chip and the ThinPrep assay and had confirmed histological diagnoses, we evaluated the diagnostic accuracy of the PANArray HPV test based on direct sequencing and clinical performance compared to the ThinPrep alone and co-testing. HR-HPVs were identified in 212 (70.7 %) patients by the PANArray HPV test. The results of the PANArray HPV test and direct sequencing for detecting HR-HPVs were in almost perfect agreement, consistent in 95.3 % of the cases (k = 0.89). HR-HPVs were more commonly detected by the PANArray HPV assay in patients with high-grade squamous intraepithelial lesions (HSILs) or worse (p < 0.001, both) by cytological and histological examinations. The PANArray HPV test had higher sensitivity (91.7 %) than the ThinPrep (52.6 %) but co-testing increased the sensitivity for predicting HSIL or worse cervical lesions to 99.2 %. In conclusion, the PANArray HPV test accurately detected HR-HPVs determined by cytological and histological examinations to be HSIL or worse cervical lesions. The PANArray HPV assay alone was more sensitive than the ThinPrep alone for detecting HSIL or worse cervical lesions, however, co-testing enhanced the sensitivity. Co-testing is more useful for screening HSIL or worse lesions than use of either the ThinPrep or PANArray HPV genotyping alone.

Background The optimal technique for removal of diminutive or small colorectal polyps is debatable. Objective To compare the complete resection rates of cold snare polypectomy (CSP) and cold forceps polypectomy (CFP) for the removal of adenomatous polyps ≤7 mm. Design Prospective randomized controlled study. Setting A university hospital. Patients A total of 139 patients who were found to have ≥1 colorectal adenomatous polyps ≤7 mm. Interventions Polyps were randomized to be treated with either CSP or CFP. After the initial polypectomy, additional EMR was performed at the polypectomy site to assess the presence of residual polyp tissue. Main Outcome Measurements Absence of residual polyp tissue in the EMR specimen of the polypectomy site was defined as complete resection. Results Among a total of 145 polyps, 128 (88.3%) were adenomatous polyps. The overall complete resection rate for adenomatous polyps was significantly higher in the CSP group compared with the CFP group (57/59, 96.6% vs 57/69, 82.6%; P = .011). Although the complete resection rates for adenomatous polyps ≤4 mm were not different (27/27, 100% vs 31/32, 96.9%; P = 1.000), the complete resection rates for adenomatous polyps sized 5 to 7 mm was significantly higher in the CSP group compared with the CFP group (30/32, 93.8% vs 26/37, 70.3%; P = .013). Limitations Single-center study. Conclusion CSP is recommended for the complete resection of colorectal adenomatous polyps ≤7 mm. (Clinical trial registration number: NCT01665898.)

Background: This study investigated survival differences following intra-operative frozen-section examination of bile duct resection margins and final longitudinal margin status (LMS) in distal bile duct cancer confined to the intra-pancreatic portion. No studies have examined the relationship between LMS and survival for distal bile duct cancer. Methods: Overall, 193 patients underwent Whipple's operation for curative resection of distal bile duct cancer from 2008 to 2016 at the Asan Medical Center, Seoul, Republic of Korea. Patients were sorted into 2 and 3 groups according to LMS of frozen-sections and LMS of the final pathological specimen results: R0 on first bile duct resection (Primary R0), R0 after additional resection (Secondary R0), and no evidence of residual carcinoma (FR0), carcinoma in situ or high-grade dysplasia (FR1-CIS/HGD), or invasive carcinoma (FR1-INV). Survival and prognostic factors according to LMS were analyzed. Findings: There were no differences between primary R0 and secondary R0 in 5-year overall survival (OS) (60.8% vs. 46.1%, P = 0.969) or diseasefree survival (DFS) (54·6% vs. 54·9%, P = 0·903). The 5-year OS after FR0, FR1-CIS/HGD, FR1-INV were 59·3%, 59·5%, 14·3%, respectively. There was no difference between FR0 and FR1-CIS/HGD (P = 0·842). Final margin status of the bile duct was an independent prognostic factor by multivariable analyses. Interpretation: If R0 of final longitudinal margin status was achieved, it would help to improve survival regardless of R0 through additional resection. And, it should be avoided remaining invasive cancer at the longitudinal margin whenever possible. Funding Statement: This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (grant number: HI14C2640). Declaration of Interests: The authors declare no competing interests in relation to this study. Ethics Approval Statement: Data collection and analysis were performed according to the institutional guidelines, which conformed to the ethical standards of the Declaration of Helsinki. Institutional Review Board approval was obtained on December 22, 2017 (No. 2017-1407).

Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P

The clinicopathological and prognostic significance of CDX2 and mucin expression have not been comprehensively evaluated in small intestinal adenocarcinoma. Immunohistochemical microarray analyses of CDX2, MUC1, MUC5AC, and MUC6 protein expressions in 189 surgically resected small intestinal adenocarcinoma cases were examined and compared with various clinicopathologic variables, including survival. CDX2, MUC1, MUC5AC, and MUC6 expressions were observed in 43.4% (82 patients), 37.6% (71), 31.7% (60), and 21.7% (41) of patients, respectively. Whereas CDX2 expression was found to be associated with low-grade tumors (P=0.034), fewer nodal metastases (P=0.019), and less perineural invasion (P=0.049) in small intestinal adenocarcinoma patients, patients expressing MUC1 tended to demonstrate high-grade (P=0.021) and nodular or infiltrative (P=0.020) tumors. On the basis of the combined CDX2, MUC1, MUC5AC, and MUC6 expression patterns, small intestinal adenocarcinoma patients were further classified as intestinal (CDX2+/MUC1-; 29.6%), pancreatobiliary (CDX2-/MUC1+; 23.8%), mixed (CDX2+/MUC1+; 13.8%), gastric (CDX2-/MUC1-/MUC5AC+ or MUC6+; 13.8%), or null (CDX2-/MUC1-/MUC5AC-/MUC6-; 19.0%). Among these immunophenotypes, intestinal-type patients demonstrated more frequent distal (jejunal or ileal; P=0.033), tubular (P=0.039), and low-grade tumors (P=0.004) and significantly better survival according to univariate (P

The possibility to isolate synovial fluid-derived mesenchymal stem cells (SFMSCs) from patients with degenerative arthropathy has been an interest since synovial fluid (SF) from osteoarthritis (OA) patients offered a unique stem-cell resource for therapeutic applications. In this study, we successfully isolated, cytogenetically and molecularly characterized, and followed the differentiation potency of human mesenchymal stem cells (MSCs) from SF. The morphology of proliferating SFMSCs showed fibroblast-like morphology, and both the population doubling time (DT) and viability of MSCs from bone marrow, adipose, and SF did not differ. The immunophenotype of SFMSCs was confirmed by the positive expression of CD44, CD73, CD90, CD105, and CD106 by flow cytometry and immunocytochemistry, and the expression of the hematopoietic markers, CD34 and CD45, was not found. In all MSCs from three different origins, we measured the mRNA expression of developmentally important transcript factors such as KLF4, c-Myc, Sox2, a...

Background Glomangiopericytoma belongs to the category of borderline/low-malignant-potential tumors of the sinonasal tract, but no studies about prognosis have been reported. Methods To define the characteristics of glomangiopericytoma and to identify its prognostic factors, a systematic review was performed. A total of 337 cases of glomangiopericytomas were analyzed. Results Patients with glomangiopericytoma demonstrating resection margin involvement and receiving radiotherapy/chemotherapy had a significantly worse disease-free survival time (P = .014 and .006, respectively). Patients with glomangiopericytoma had a tendency toward longer overall survival when they were diagnosed at a younger age (≤60 years; P = .001), did not demonstrate marginal involvement (P = .032), recurrence/metastasis (P = .002), or radiotherapy/chemotherapy (P = .010), and had a right-sided tumor (P

Objectives: Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. Methods: Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. Results: Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p = 0.009) and advanced disease stage (p = 0.013), and was more frequently observed in distal than duodenal tumors (p = 0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT3 and pT4; p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. Conclusion: Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage.

Small intestinal adenocarcinoma is a rare malignant neoplasm, and its clinicopathologic characteristics have not been well elucidated. A total of 197 small intestinal adenocarcinoma cases were collected from 22 institutions in South Korea and were evaluated for clinicopathologic factors that affect the prognosis of small intestinal adenocarcinoma patients using univariate and multivariate analyses. The mean patient age was 59 years, and the male-to-female ratio was 1.7:1. Tumors were located in the duodenum of 108 cases (55%), the jejunum in 59 (30%), and the ileum in 30 (15%). Predisposing conditions were observed in 23 cases (12%), including 17 cases with sporadic adenomas, 3 with Peutz-Jeghers syndrome, 2 with Meckel diverticulum, and 1 with Crohn disease. Synchronous or metachronous malignant tumors were identified in 31 cases (16%), including 13 colorectal and 10 stomach cancers. About 90% of tumors were classified as either pT3 (63 cases) or pT4 (112 cases). The median survival time for all small intestinal adenocarcinoma patients was 39.7 months. Compared with small intestinal adenocarcinomas without accompanying sporadic adenomas, small intestinal adenocarcinomas with accompanying adenomas were more well differentiated (P < .0001), with a more polypoid growth pattern (P < .0001), a lower pT classification (P < .0001), less perineural invasion (P = .01), and less lymphatic invasion (P = .03). Small intestinal adenocarcinoma patients with associated sporadic adenomas (77%) had a significantly better 5-year survival rate than those without sporadic adenomas (38%, P = .02). By univariate analysis, small intestinal adenocarcinoma patients had significantly different survival based on pT classification (P = .003), lymph node metastasis (P < .0001), distal location (jejunal and ileal carcinomas) (P = .003), retroperitoneal tumor seeding (P < .0001), vascular invasion (P = .007), lymphatic invasion (P = .001), peritumoral dysplasia (P = .004), and radiation therapy (P = .006). By multivariate analysis, lymph node metastasis (P = .01) and distal location (P = .003) were independent predictors of a worse prognosis. In conclusion, (1) small intestinal adenocarcinomas are diagnosed at an advanced disease stage; therefore, the development of strategies for detection at an earlier stage is needed. (2) Small intestinal adenocarcinoma patients with an adenomatous component had a better survival than those without an adenomatous component. (3) Lymph node metastasis and distal location (jejunum and ileum) of tumor are the most important independent prognostic factors.

Background Ezrin is a cytoskeleton linker protein that is actively involved in regulating the growth and metastatic capacity of cancer cells. The purpose of the study was to assess the expression pattern of ezrin in normal skin and various epithelial neoplasms. Methods We used immunohistochemical techniques to examine the expression of ezrin in paraffin-embedded tissues of squamous cell carcinoma (n = 23), basal cell carcinoma (n = 10), Bowen’s disease (n = 10), actinic keratosis (n = 10), keratoacanthoma (n = 9), seborrheic keratosis (n = 5), psoriasis vulgaris (n = 5), and normal control skin (n = 5). Results In Bowen’s disease, actinic keratosis, keratoacanthoma, and seborrheic keratosis, ezrin was dominantly expressed in the cell membrane except for the cornified layer. In squamous cell carcinoma (SCC) specimens, the percentage of ezrin-positive cells was increased compared with Bowen’s disease, actinic keratosis, keratoacanthoma, and seborrheic keratosis. Especially in SCC samples, ezrin expression was markedly expressed in the cytoplasm. In addition, there was a correlation between the pattern of ezrin expression and tumor differentiation in SCC. Basal cell carcinoma showed intense and diffuse staining especially in the solid growth pattern. Conclusions Our findings suggest that dysregulation of ezrin may be important in the development of cutaneous epithelial malignancies and tumor grade. We suggest that the cytoplasmic localization of ezrin may be useful in the diagnosis of skin SCC.

Basaloid squamous cell carcinoma (BSCC) is often founded in the head and neck region. However, BSCC in the sinonasal tract is rare. We report here on the case of a 58-yr-old woman who presented with nasal obstruction and epistaxis. Computed tomography and examination of the nasal cavity revealed a tumor mass that originated from the right inferior turbinate with erosion of the nasal floor. The tumor that was attached to the inferior turbinate, the lateral nasal wall and the eroded right side hard palate, and so all this was resected. Histopathologic examination of the excised tumor confirmed BSCC in the nasal cavity. We report here on a nasal cavity BSCC that was treated with partial maxillectomy only.

Signet ring cell carcinoma of the gallbladder is a rare variant of adenocarcinoma of the gallbladder. CT findings of signet ring cell carcinoma have been rarely reported. However, to our knowledge, signet ring cell carcinoma of the gallbladder with intramural tumoral calcifications has not been reported. Here, we present a case of mucin-producing signet ring cell carcinoma of the gallbladder which appeared as low attenuated diffuse gallbladder wall thickening with intramural calcifications and metastatic conglomerated lymphadenopathy.

Primary squamous cell carcinoma of the thyroid gland is very rare and its histogenesis is poorly defined so far. Although there have been some cases of squamous cell carcinoma with variant types of papillary thyroid carcinoma (PTC), the present case is the first primary squamous cell carcinoma with classic PTC to be reported. A 43-year-old woman presented with a 20 year history of neck mass. Neck ultrasound indicated a 6 × 4 × 3 cm large mass. The patient underwent total thyroidectomy. Histopathology indicated a well-differentiated squamous cell carcinoma and squamous metaplasia in conjunction with classic PTC. On immunohistochemistry cytokeratin 7 was positive in papillary carcinoma and squamous metaplasia, thyroglobulin was positive only in papillary carcinoma, and p63 was positive in squamous metaplasia and squamous cell carcinoma. Postoperatively, the patient received 59.4 Gy adjuvant radiotherapy, hormonal therapy and radioactive iodine therapy. At 8 months after surgery the patient remained disease free.

BACKGROUND/AIMS Several simple tests for hepatic fibrosis employ indirect markers. However, the efficacy of using direct and indirect serum markers to predict significant fibrosis in clinical practice is inconclusive. We analyzed the efficacy of a previously reported indirect marker of hepatic fibrosis - the aspartate aminotransferase to platelet ratio index (APRI) - in patients with nonalcoholic chronic liver diseases (CLDs). METHODS A total of 134 patients who underwent a percutaneous liver biopsy with a final diagnosis of chronic hepatitis B (n=93), chronic hepatitis C (n=18), or nonalcoholic fatty liver disease (n=23) were enrolled. A single-blinded pathologist staged fibrosis from F0 to F4 according to the METAVIR system, with significant hepatic fibrosis defined as a METAVIR fibrosis score of >/=2. RESULTS The mean area under the receiver operating characteristic curve (AUROC) of APRI for predicting significant fibrosis in nonalcoholic CLDs was 0.84 [95% confidence interval (CI), 0.78-0.91]. APRI yielded the highest mean AUROC in the patients with chronic hepatitis B (0.85; 95% CI, 0.771-0.926). The positive predictive value of APRI >/=1.5 for predicting significant fibrosis was 89%. The negative predictive value of APRI

Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wild-type KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

We report 3 cases of synovial sarcoma with rhabdoid features, initially diagnosed as adult rhabdoid tumors. Two women (case nos. 1 and 2, 35 years and 27 years of age, respectively) and one man (case no. 3, 26 years of age) presented to their physicians with right flank pain. On physical examination, a poorly defined, firm, palpable mass was found in the upper right quadrant of the abdomen in all cases. Sonography and computed tomography revealed solid, cystic masses in the right kidneys that ranged in size from 8.5 to 20.0 cm. Right radical nephrectomies were performed in all patients. One patient died of disease, and the other two patients were alive and disease-free after chemotherapy and radiotherapy. Microscopic examination revealed that the tumors were composed mostly of rhabdoid cells with eccentrically located nuclei, prominent nucleoli, and eosinophilic cytoplasm. We also found areas of fasciculated spindle cells, sharply separated from or irregularly admixed with areas of rhabdoid cells. There was tumor necrosis, but no epithelial areas were seen. Hemangiopericytic vasculature was at least focally observed in all cases. The tumor cells were positive for CD99 and bcl-2 in all cases and for CD56 in two cases and negative for CD34 and smooth muscle actin in all cases. The cells in case no. 1 were focally positive for cytokeratin. To verify the possibility of synovial sarcoma with rhabdoid features, reverse transcriptase polymerase chain reaction using RNA extracted from frozen tissue in case no. 1 and formalin-fixed, paraffin-embedded tissue in case nos. 2 and 3 was performed. SYT-SSX2 transcripts were detected in all 3 cases. These cases indicate that synovial sarcoma of the kidney should be considered in the differential diagnosis of mesenchymal kidney tumors with prominent rhabdoid features. A subset of adult rhabdoid tumors may be a rhabdoid variant of synovial sarcoma, and molecular studies to detect SYT-SSX fusion transcripts are recommended for an accurate diagnosis.

Detecting high-risk (HR) HPV is important for clinical management of women with persistent HPV-positive and Pap-negative results. The Cobas 4800 HPV test is the first FDA-approved HPV DNA test that can be used alone as a first-line screening tool. The HPV 9G DNA chip test is a PCR-based DNA microarray assay. We evaluated the patients of consecutive HPV-positivity on HPV 9G DNA chip test without cytologic abnormalities. We then compared the performances of HPV 9G DNA chip and the Cobas 4800 HPV tests for detecting HR HPV with each other and confirmed HPV genotyping using direct sequencing. All 214 liquid-based cytology specimens were collected from 100 women with consecutive HPV-positive and Pap-negative results on the HPV 9G DNA chip test between May 2012 and Dec 2013, but only 180 specimens were available for comparing HPV test results. The HPV 9G DNA chip and the Cobas 4800 HPV tests agreed with each other in 81.7% of the samples, and the concordance rate was greater than 97.2% for detecting HPV-16 or -18. For HR genotypes other than HPV types 16 and 18, the two tests agreed for 81.1% of the samples. The sensitivity of both assays for detecting HR HPV was 100%, regardless of HR genotypes. The HPV 9G DNA chip test may be as effective as the Cobas 4800 HPV test in detecting HR HPV, and has a similar ability to identify HPV-16 and -18.

e15126 Background: Recent findings demonstrated that microsatellite instability high (MSI-H) colon cancer contains high T-cell infiltration and upregulated expression of multiple immune checkpoints. The aim of this study was to reveal the prognostic impact of MSI-H colon cancer showing immune checkpoint protein expressions, which are good candidates for immunotherapy. Methods: From January 2011 to April 2015, we included 98 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Medical Center. Inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1) and indolamine 2’3’-dioxygenase (IDO) expression status were retrospectively analyzed using immunohistochemistry (IHC). Positivity in tumor cells (T) and immune cells (I) were separately evaluated. IHC values were determined to be positive when moderate or strong intensity of the membranous to cytoplasmic staining pattern were shown in more than 5% of the tumor cells or immune cells. Results: Among the 93 patients, 22 patients (23.9 %) and 63 (68.5%) were determined as PD-L1(T) positive and PD-L1 (I) positive, while 12 (13.2%) and 42 (45.7%) were determined as LAG-3(I) positive and PD-1 (I) positive. Twenty-seven patients (29.3%) and 66 (71.7%) were determined as CTLA-4 (T) positive and CTLA-4 (I) positive, while 66 (71.7%) and 26 (28.3%) were determined as IDO (T) and IDO (I) positive. During median follow-up duration of 39 months, 16 (17.4%) patients experienced recurrence. LAG-3 (I) positivity was significantly associated shorter relapse-free survival (p = 0.016). Moreover, LAG-3 expression was significantly correlated with PD-L1 (T) expression (p = 0.003). Co-expression of PD-L1 and LAG-3 showed worse prognosis for relapse-free survival (p < 0.001). Conclusions: In conclusion, LAG-3 positivity showed worse prognosis in patients with MSI-H colon cancer. Potential differential therapeutic implications LAG-3 should be further investigated.

Background Paragonimiasis infestation is endemic mostly to Asia, Africa and South and Central America and commonly found in the lung. It is extremely rare in soft tissue. Case A case of paragonimiasis occurred in a 66-year-old woman who presented with a left, painful, 2-cm-diameter breast mass and had a history of eating uncooked freshwater crabs. On mammography, an ill-defined, round, isodense mass was detected without calcification. Hemorrhagic material was aspirated by fine needle aspiration (FNA) of the breast mass, which contained many parasitic eggs. They were about 90 microns long, ovoid, yellowish brown, transparent and thick shelled, with a flattened operculum at 1 end. The breast mass was completely excised. Many collapsed eggs of Paragonimus infiltrated the lobules and fibroadipose tissue, with accompanying abscess formation. To confirm the diagnosis, serologic testing for paragonimiasis was performed; it was positive for Paragonimus antibody. Conclusion Paragonimiasis very rarely presents as a breast mass and can be diagnosed by FNA.

Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1β, Wilms' tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient's survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%, respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival (P

BACKGROUND/AIMS Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC. METHODOLOGY A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC). RESULTS The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status. CONCLUSIONS The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).

Gastritis cystica profunda (GCP) is a rare disease which shows multiple cystic gastric glands within the submucosa of the stomach. GCP lesions mainly develop at the site of gastroenterostomy and exhibit benign behavior. However, there have been a number of debates over its malignant potential. Several reports have documented GCP accompanied by gastric carcinomas, but the relationship between the two conditions remains uncertain. Here we report two cases of GCP with dysplasia accompanied by synchronous multiple early gastric cancers without previous gastric surgery.

We report an autopsy case of a male fetus with Adams-Oliver syndrome. His mother was a healthy, 31-year-old woman and her family and past histories were unremarkable. Therapeutic termination was done at 28(+6) weeks gestational age due to oligohydramnios detected by antenatal ultrasonography. Chromosomal study revealed normal karyotype. On autopsy, characteristic transverse terminal defect of four extremities was found. Both feet were short and broad. All toes were rudimentary with no nails and fingers were irregularly short. On infantogram, all toe-bones were stubby and rudimentary. The middle and terminal phalanges of 2nd, 3rd & 5th fingers and the terminal phalange of 4th finger on the right hand were absent. The middle and terminal phalanges of 2nd & 5th fingers and terminal phalange of 3rd finger were defected on the left hand. His abnormalities were consistent with features of Adams-Oliver syndrome, which has not been reported in Korea.

We report a case of a 70-year-old man with lymphoma of the ulnar nerve that presented as a palpable mass on his left forearm and wrist. He had a history of oral lymphoma with complete remission after chemotherapy and radiotherapy. The lesion appeared sonographically as a hypoechoic mass mimicking a cyst encasing the ulnar nerve. However, the mass showed vascularity on color Doppler sonography. Lymphoma involving the peripheral nervous system is very rare. 1 To the best of our knowledge, there has been no report of sonographic findings that describe lymphoma involving the peripheral nerves. In this report, we describe the sonographic features of a case involving lymphoma of the ulnar nerve and correlate sonography with magnetic resonance image, positron emission tomography/computed tomography, and histopathologic examination.

Background There have been still few valuable markers that can be used as indirect markers of liver fibrosis in chronic hepatitis B. Aims This study aimed to evaluate efficacy of several indirect markers of liver fibrosis and to identify the most valuable test in chronic hepatitis B. Patients and methods A total of 264 patients with chronic hepatitis B were consecutively enrolled. Fibrosis was staged by a single blinded pathologist according to the METAVIR system. Significant fibrosis was defined as stage ≥2. We investigated diagnostic accuracy of four indirect markers including aspartate aminotransferase to platelet ratio index for predicting significant fibrosis. Results Mean age was 28 years. 53% (141/264) had significant hepatic fibrosis. Of indirect markers, aspartate aminotransferase to platelet ratio index yielded the best area under the receiver operating characteristic curve (0.86; 95% confidence interval, 0.82–0.91). Positive predictive value/negative predictive value at 0.5, 1.5 and 2.0 of aspartate aminotransferase to platelet ratio index score for predicting significant fibrosis were 63%/91%, 83%/74% and 86%/65%, respectively. The odds ratio for aspartate aminotransferase to platelet ratio index ≥1.4 relative to less than aspartate aminotransferase to platelet ratio index of 1.4 was 17.971 (p Conclusions Of simple markers already developed in chronic hepatitis C, aspartate aminotransferase to platelet ratio index may be the most accurate and simple marker for predicting significant fibrosis in chronic hepatitis B.