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The diagnosis of type 2 autoimmune pancreatitis (AIP) is dependent on typical radiologic imaging and the presence of the granulocytic epithelial lesion (GEL), which is characterized by ductal neutrophilic infiltration with or without neutrophilic acinar infiltration.We evaluated GEL and related clinicopathologic factors in 165 resected heterotopic pancreata (HPs) [57 gastric (35%), 56 duodenal (34%), 30 omental (18%), and 22 jejunal (13%)] and 29 matched orthotopic pancreata routinely examined during surgery.GEL was noted in 8% (13/165) of HPs, including ductal epithelial (6/13, 46%) and intraluminal (8/13, 62%) neutrophilic infiltrations. However, there was no GEL in orthotopic pancreata. Abdominal pain was observed in 6 (46%) patients with GEL-positive HPs. GEL was more commonly observed in HPs having symptoms (p = 0.029), a larger size (p = 0.028), and an infiltrative growth pattern (p = 0.006). In addition, periductal lymphoplasmacytic infiltration and fibrosis (both p 0.001), interstitial fibrosis (p = 0.017), acinar neutrophilic infiltration (p = 0.032), venulitis (p = 0.050), acinar ductal metaplasia (ADM; p = 0.040), and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; p 0.001) were more commonly seen in HPs with GEL than in those without GEL. Inflammatory bowel disease was present only in one patient with GEL-negative HP.GELs are detected in a subset of HPs without clinical evidence of AIP. Therefore, for the diagnosis of AIP, GEL should be carefully interpreted with the context of other histologic, clinical, and radiologic findings.

The T category of distal extrahepatic bile duct carcinoma (DBDC) is based on invasion depth from the basal lamina to the deepest infiltrating tumor cells. Recently, invasive tumor thickness (ITT) was proposed, defined as maximal vertical distance of invasive tumor components regardless of the basal lamina. We compared the predictive value of T category, and ITT grading in 424 surgically resected DBDCs. DBDCs were categorized as 6 Tis (1.4%), 134 T1 (5 mm; 31.6%), 204 T2 (5 to 12 mm; 48.1%), and 80 T3 (12 mm; 18.9%). With ITT, there were 6 G0 (no invasion; 1.4%), 3 G1 (1 mm; 0.7%), 90 G2 (≥1 and5 mm; 21.2%), 188 G3 (≥5 and10 mm; 44.4%), and 137 G4 (≥10 mm; 32.3%). The 5-year survival rates of T1, T2, and T3 were 58.9%, 44.2%, and 18.2%, and those of ITT G1, G2, G3, and G4 were 33.3%, 54.1%, 51.6%, and 26.7%, respectively. The T category discriminated patient survival by overall (P0.001) and pairwise (T1 vs. T2, P=0.007; T2 vs. T3, P0.001) comparisons. ITT grading distinguished survival by overall and between G3-G4 (both P0.001), with no survival differences observed between G1-G2 and G2-G3 comparisons. The T category more accurately discriminated patient survival than ITT grading. To determine the T category for DBDCs, (1) longitudinal sectioning on gross examination, especially for DBDCs with large papillary or nodular growth patterns; (2) evaluation of serial sections or alternative hematoxylin and eosin slides; (3) use of a straight or curved baseline depending on the shape of the peritumoral normal bile duct wall and/or the basal lamina of the peritumoral normal biliary epithelia/biliary intraepithelial neoplasias are recommended.

Background: Invasive breast carcinoma with a choriocarcinomatous pattern (IBC-CP) is extremely rare, and its molecular basis is yet unclear. The choriocarcinomatous pattern is characterized by the biphasic arrangement of multinucleated syncytiotrophoblast-like cells around clusters of monotypic tumor cells in a hemorrhagic background, along with β-human chorionic gonadotropin (β-hCG) expression. The differentiation of IBC-CP from metastatic choriocarcinoma of the breast (MC-B) is difficult due to the histologic similarity. Methods: Based on a literature review and our own case, the clinicopathologic differences between IBC-CP patients (n = 17) and MC-B patients (n = 8) were analyzed. Moreover, in our case of IBC-CP, next-generation sequencing (NGS) comparative analysis was conducted for both choriocarcinomatous and invasive breast carcinoma (IBC) components. Results: Compared to the MC-B patients, the IBC-CP patients were older (p < 0.001) and less frequently had past histories of gestational trophoblastic disease/pregnancy/abortion (p = 0.001) and distant metastases (p = 0.005). Our case, a 49-year-old female patient, presented with masses in the right breast and axilla. Following neoadjuvant chemotherapy, a radical mastectomy found an 8.5-cm-sized tumor. Microscopically, multinucleated syncytiotrophoblast-like cells were observed around mononuclear tumor cells with hemorrhage and necrosis. Some tumor cells showed β-hCG immunopositivity, which was compatible with IBC-CP. NGS results showed a missense mutation in exon 5 of the TP53 gene in both the choriocarcinomatous and IBC components. Meanwhile, copy number loss in the PTEN gene was only identified in the choriocarcinomatous components. Conclusion: The present IBC-CP case is triple-negative breast cancer with TP53 mutation. The PTEN gene may be associated with choriocarcinomatous differentiation. Obtaining a medical history is mandatory to exclude metastatic lesions.

Context.— The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. Objective.— To assess TME-based prognostic risk in AC. Design.— We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. Results.— TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). Conclusions.— TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.

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.

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.

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.

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.

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.

The influence of 0.015 wt% Ti addition on the formation of MX precipitates and the creep resistances of a reduced activation ferritic/martensitic (RAFM) steel has been studied. 0.1 wt% Ta was also added as same as conventional RAFM steels. Transmission electron micrographs taken from extraction replicas indicated that the area fraction of MX particles in Ta/Ti-added RAFM steel was 2.3 times higher than that in the reference steel. Atom probe tomography was employed to identify the types of MX precipitates and their interactive distribution. By using isoconcentration surfaces with different elemental concentration values, it was newly found that there are three types of MX precipitates, i.e. (Ta,V)-rich MX, Ti-rich MX and W-rich MX in the Ta/Ti-added RAFM steel. They appeared to be distributed independently in the matrix. However, in some cases, smaller sized (Ti or W)-rich MX particles were in contact with large (Ta,V)-rich MX particle. The creep rupture life of the Ta/Ti-added RAFM steel was significantly improved, as compared with the reference steel. The enhanced creep resistance can be rationalized in terms of a high density of dislocations, which were produced by a strong interaction with a higher fraction of the nano-sized MX particles within laths.

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.

In this study, the selective electron beam melting (SEBM) process was used to fabricate Inconel 718 superalloy, and their microstructures and creep resistances were investigated. The proper SEBM condition ensuring a relative density higher than 99.9% was found in electron beam current range of 24–30 mA at a scanning speed of 4500 mm/s and a preheat temperature of 1025 °C, from which the SEBMed Inconel 718 exhibited an unidirectional columnar grain microstructure with a strong texture along building direction. It was suggested that the local thermal condition during solidification after SEBM facilitates a continuation of epitaxial growth of crystals on layer beneath. The γ″ precipitates formed in the as-built condition regardless of focus offset, and their size increased with increasing focus offset from 1 to 12 mA. The creep rupture life of the as-built sample fabricated with focus offset of 12 mA showed 2 times longer than that of conventional forged Inconel 718 subjected to full heat treatment under creep condition of 650 °C/700 MPa. EBSD analysis on the crept samples indicated that strain accumulation was significant at the porosities and the high-angle grain boundaries. Additionally, the grain boundaries inclined to loading axis were more damaged during creep. The γ″ particles were occasionally sheared by matrix dislocations with Burger vector of a/2 , without leaving stacking faults behind. The enhanced creep resistance of SEBMed Inconel 718 superalloy can be attributed to the columnar microstructure with a strong texture and the high density of dislocations resulted from strong interaction with the γ″ particles.

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).

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.

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

Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs.

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.

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.

This study showed increased expression of p63 and survivin in cholesteatoma. Our finding indicates a putative role of p63 and survivin in the development of certain cholesteatomas.Keratinocytes in cholesteatoma demonstrate uncoordinated hyperproliferation, migration, and invasion properties. p63 is a p53 homologue and a marker expressed in replicating keratinocytes. Survivin is an inhibitor of apoptosis protein that is abundantly expressed in most solid and hematologic malignancies. The purpose of this study was to investigate the differential expression of p63 and survivin in human middle ear cholesteatoma epithelium.The expression levels of p63 and survivin protein were examined by immunohistochemical analysis of 40 cholesteatomas and 5 skin tissues obtained from patients during ear surgery.Expression of p63 protein was diffusely observed in entire samples of cholesteatoma, especially in acquired cholesteatoma, compared with the control group. Congenital cholesteatoma showed variable p63 reactivity in a basal cell-like pattern. Primary and recurrent cholesteatomas showed no significant difference in p63 expression. Survivin was detected in 31 of 40 cholesteatoma samples. Acquired cholesteatomas showed especially increased survivin expression compared with congenital cases. The expression of p63 was correlated with survivin expression.

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.

The incidence of ectopic Leydig cells (LCs) has been reported to be 40% to 90%. Several theories have been proposed to account for ectopic LCs, including in situ differentiation, migration from testicular interstitium, and trapping of peritubular LCs in the tunica propria of the seminiferous tubule during its thickening. To document the nature of ectopic LCs and to compare them with interstitial LCs, Sertoli cells, epididymal cells, mesothelial cells, and epithelial cells in rete testis, immunostainings with calretinin, CD10, inhibin, CK7, and CK20 were performed in 40 cases of orchiectomy specimens using tissue microarray sections. In addition, the frequency of ectopic LCs was evaluated. Of the 40 orchiectomy specimens, 14 cases demonstrated ectopic LCs with an incidence of 35%. Inhibin was positive in more than half of ectopic LCs (9/14, 64.3%) and in almost all interstitial LCs. Calretinin was positive in most of ectopic LCs (12/14, 85.7%) as well as in most of normally located interstitial LCs and mesothelial cells and some of rete testis epithelial cells. The ectopic and interstitial LCs as well as Sertoli cells were negative for CK7, CK20, and CD10. CK7 was positive in all epididymal cells and in most mesothelial cells and epithelial cells in rete testis. CD10 was positive in some of epididymal cells and epithelial cells in rete testis. CK20 was negative in all cells in the testis and epididymis. Ectopic LCs showed similar staining patterns to interstitial LCs with positive immunoreactivity for calretinin and inhibin. In this study, the frequency of ectopic LCs was 35%. The lower incidence in this study was most likely because of the limited sampling. Immunohistochemically, ectopic LCs showed identical immunohistochemical patterns with those of interstitial LCs. Calretinin appeared to be more sensitive but less specific than inhibin for LCs. Because calretinin is frequently positive in cells other than ectopic or interstitial LCs, a precaution is required to differentiate LCs from mesothelial cells and rete testis epithelial cells. Based on our study, we could not add anything else of what is known in regard to the histogenesis of ectopic LCs. The current theories including in situ differentiation, migration from testicular interstitium, and trapping of peritubular LCs in the tunica propria of the seminiferous tubules during its thickening seem to be valid histogenetic theories.

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

We investigated signal transducer and activator of transcription-5 (STAT5) activation status in renal cell carcinoma (RCC) and the role of transforming growth factor-beta (TGF-beta) in the process.Twenty normal and RCC tissues were obtained from radical nephrectomy specimens for the assessment of expressions of phosphorylated STAT5 (p-STAT5) and TGF-beta1 (Western blot) and for localization and assessment of their relationship (immunohistochemical and immunofluorescence stains). By using four RCC cell lines and four primary cultured cells, the effect of TGF-beta1 and/or interleukin-2 (IL-2) on the expressions of p-STAT5 were analyzed.In RCC samples, expression of p-STAT5 was significantly reduced while expression of TGF-beta was enhanced compared with normal kidney tissues (P0.001 and P = 0.003, respectively). P-STAT5 was observed almost exclusively in the nuclei of normal kidney tissues while TGF-beta was identified in the cytoplasm of cells of both tissues reflecting the Western results. In both RCC cell lines and cells from primary cultures, treatment with TGF-beta or antibody did not significantly alter STAT5 activation. However, TGF-beta significantly suppressed IL-2-induced STAT5 activation, whereas anti-TGF-beta antibodies enhanced IL-2-induced STAT5 further.STAT5 activation is suppressed in RCC compared with normal renal parenchyma. It may be attributed to the RCC-derived TGF-beta which also interferes with IL-2-induced STAT5 pathway activation.

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.

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas. To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300+/-1200 mum) than noncretas (1500+/-1200 microm, P0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly. These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.

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.

Aims: To determine the utility of p57 kip2 in the diagnosis of hydatidiform mole. p57 kip2 protein is a cyclin-dependent kinase inhibitor (CDKI) and is strongly paternally imprinted, being expressed from the maternal allele. It has been hypothesized that complete mole (CHM) with only the paternal genome would display reduced or nearly absent expression of p57 kip2 compared to partial mole (PHM) having both paternal and maternal genomes. Methods and results: The immunobistochemical expression of p57 kip2 protein was investigated using paraffin-embedded tissue sections in histologically unequivocal cases of CHM (n = 51), PHM (n = 7), invasive mole (n = 1), and hydropic miscarriage (n = 2), as well as in histologically undetermined cases (n = 9). In the histologically unequivocal complete and invasive moles, expression of p57 kip2 was absent except for one case in which villous cytotrophoblast covering the villous stroma was positive (51/52) as well as villous stromal cells (51/52). In contrast, it was strongly and continuously expressed in both villous cytotrophoblast and stromal cells in all cases of PHM and hydropic miscarriage. Among the nine histologically undetermined cases, five cases showing p57 kip2 immunopositivity and hyperploid DNA were classified as PHMs, two cases showing p57 kip2 immunonegativity and hyperploidy as CHMs, and two cases with p57 kip2 immunopositivity and diploid DNA as hydropic miscarriage and diploid PHM, respectively, upon review of the histopathological findings. Intermediate trophoblast forming trophoblastic columns or anchoring villi and extravillous trophoblast at the implantation site showed variable expression of p57 kip2 in all gestational conditions. Maternal decidua showed diffuse and strong p57 kip2 expression, whereas syncytiotrophoblast was completely negative in all cases regardless of the diagnosis. Conclusions: In summary, p57 kip2 immunostaining results correlated well with morphological features of molar pregnancies and were helpful in determining histologically equivocal cases.

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.