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In the era of precision medicine, accurate and reproducible assignment of cell-of-origin (COO) in diffuse large B-cell lymphoma patients has become important. The Lymph2Cx assay is accurately determining COO by analyzing RNA expression of 20 selected genes while the Hans algorithm based on immunohistochemistry is the most popular method for routine daily diagnosis. However, there are discrepancies between the 2 methods, which need to be evaluated for better correlation. We prospectively analyzed 156 cases of diffuse large B-cell lymphoma, not otherwise specified to analyze the characteristics of discrepancy groups of COO determined by Lymph2Cx and Hans algorithm. We investigated the pattern and cause of discrepancy of COO assigned by the 2 methods. Hans algorithm classified 50 cases (32%) as germinal-center B-cell-like (GCB) type and 106 cases (68%) as non-GCB type. Lymph2Cx assay assigned 43 cases (28%) as GCB type, 94 cases (60%) as activated B-cell-like type, and 19 cases (12%) as intermediate/unclassified type. The agreement rate was 86% after exclusion of unclassified type. With regard to the clinicopathologic factors related with discrepancy between Hans algorithm and Lymph2Cx assay, endoscopic biopsy of the gastrointestinal tract (4/11, 36%) showed higher discrepancy rate (P=0.052). Immunophenotypically, CD10/BCL6/MUM1 GCB type and CD10/BCL6//MUM1 (=30%, low level expression) non-GCB type exhibited a significantly higher discrepancy rate (6/13, 46%; 4/13, 31%) (P=0.0001). Activated B-cell-like subgroup via Lymph2Cx assay predicted poor progression-free survival (mean survival duration 28.6 mo, P=0.049) compared with the GCB and unclassified type. Hans algorithm revealed no significant difference in progression-free survival and overall survival (P=0.122 and 0.121). These results suggest that when assigning COO via Hans algorithm, CD10/BCL6/MUM1 GCB type and CD10/BCL6/MUM1 (=30%, low level) non-GCB type require careful interpretation, especially if the MUM1 staining is weak and heterogeneous in the biopsied specimen.

Background: The current American Thyroid Association risk-stratification system for papillary thyroid carcinoma (PTC) incorporates the number and size of positive lymph nodes (LNs) but places less ...

The value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established. Pre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed. High pre-NAC TILs, clinical nodal stage 0–1 (cN0–1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses. High pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Neuropilin-1 (NRP-1) is known to be related to various types of cancer and is considered a novel tumor marker or therapeutic target. The aim of this study was to identify the clinical implications of NRP-1 expression in terms of prognosis in patients with gastric cancer. A total of 265 patients who underwent radical gastrectomy for the treatment of gastric cancer from 2008 to 2011 were included in this retrospective study. NRP-1 expression of tumors was determined by immunohistochemistry. The patients’ clinicopathological characteristics, operative details, and long-term outcomes were retrospectively analyzed. A total of 181 (68.3%) patients demonstrated expression of NRP-1. No survival difference was observed according to NRP-1 expression in any patient. The patients were divided into the gland formation (GF) and the no gland formation (nGF) types, according to histology. NRP-1 expression rates were 65.6% (84/128) and 70.8% (97/137), respectively. NRP-1 expression was not an independent prognostic factor in the GF group, although patients who expressed NRP-1 had better survival outcomes. In contrast, patients who expressed NRP-1 in the nGF group had worse 5-year survival rates (p = 0.027), and NRP-1 was an independent prognostic factor in a multivariate analysis (hazard ratio, 1.923; 95% confidence interval, 1.041–3.551). NRP-1 expression in patients with nGF type gastric cancer is predictive of a poor prognosis.

Purpose Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited. Materials and methods We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)‒positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression. Results Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%). Conclusion Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.

Thymic adenocarcinoma is extremely rare. Although its histologic features have been occasionally reported, a lack of description of the cytologic features has hampered the prompt and accurate diagnosis of this condition. Herein, we describe the cytologic findings and histology of four aspiration cytology specimens of thymic adenocarcinoma. The specimens were obtained from primary tumors, metastatic lymph nodes, and pericardial effusions. All four specimens showed three-dimensional glandular clusters with a loss of polarity and nuclear overlapping. One specimen had extensive extracellular mucinous material. Three specimens contained tumor cells with intracytoplasmic vacuoles. While the specimen with extracellular mucin showed relatively mild cytologic atypia, other specimens exhibited more atypical cytologic changes: irregular nuclear membranes, a coarse chromatin pattern, and prominent nucleoli. The cytologic features were correlated with the histologic features in each case of enteric type thymic adenocarcinoma. The differential diagnosis included other thymic carcinomas, yolk sac tumors, and metastatic adenocarcinoma from the lung or colorectum.

Rationale: The radiotherapy (RT) responses of gastroenteropancreatic (GEP)-origin neuroendocrine tumors remain unclear. We report cases of favorable response after localized RT of GEP-origin neuroendocrine carcinomas (GEP-NECs). Patient concerns: 1. An 82-year-old male presented with a lower esophageal mass. Positron emission tomography computed tomography (PET-CT) scan showed a lower esophageal mass and gastrohepatic lymph nodes. 2. A 52-year-old female presented with abdominal discomfort. CT scan showed a 9.8 cm-sized enhancing mass in the lesser sac abutting the stomach, pancreas and liver. 3. A 54-year-old male patient presented with anal pain and bleeding. CT scan showed a remnant mass in the perirectal area after trans-anal excision. Diagnoses: The diagnoses of GEP-NECs were pathologically confirmed by biopsy or excision, and immunohistochemical stainings of Ki-67, CD56, synaptophysin and chromogranin-A. Interventions: 1. The patient was treated with definitive RT. 2. The patient was treated with RT after two cycles of etoposide-cisplatin chemotherapy. 3. The patient was treated with adjuvant RT. Outcomes: 1. Complete remission was achieved based on CT scan four months after RT. 2. CT scan showed partial regression of the mass with a 5 cm-diameter at six months after RT. Adjuvant chemotherapy was administered after RT. 3. The residual mass was almost completely regressed at CT scan four months after RT. Lessons: In cases of GEP-NECs, RT can be a useful treatment modality with favorable tumor response for patients with inoperable conditions or those suffering from bulky tumor masses.

Purpose Management of gastroenteropancreatic (GEP) neuroendocrine tumors with liver metastases (NETLM) presents many clinical challenges. Assessment of the extent of disease and primary tumor site is crucial for management. In this study, we investigated the primary tumor sites and prognostic factors in GEP NETLM among Korean patients. Materials and Methods We reviewed the medical records of 72 Korean patients diagnosed with GEP NETLM between January 1999 and May 2013, focusing on their clinical and pathologic characteristics. Results The most frequently encountered primary tumor sites were the pancreas (n=25, 35%), stomach (n=8, 11%), gall bladder (n=4, 6%) and rectum (n=3, 4%). Twenty-five patients (35%) had occult primary tumor. Twelve patients (17%) had histological grade G1 tumors, 30 patients (42%) had G2 tumors, and 30 patients (42%) had G3 tumors. The mean follow-up period after histological confirmation of hepatic metastases was 11.30±2.44 months for G3 tumors, 19.67±4.09 months for G2 tumors, and 30.67±6.51 months for G1 tumors. Multivariate analyses revealed that an unknown primary tumor site (p=0.001) and higher histological grade (p < 0.001) were independent prognostic indicators for shorter overall survival (OS). Most long-term survivors (OS > 24 months) had received antitumor treatment. Conclusion The primary tumor site most frequently associated with GEP NETLM was the pancreas. Unknown primary tumor and higher histological grade were independent prognostic indicators for shorter OS. Patients identified as being at a risk of shorter OS should be followed up closely.

Placental mesenchymal dysplasia (PMD) is a rare, benign condition characterized by placentomegaly and abnormal chorionic villi with vesicle formation, fibroblastic hyperplasia, and vascular abnormalities. This condition can be misdiagnosed as molar pregnancy due to similar ultrasonographic findings [1]; however, unlike molar pregnancy, a fetus is usually present and there is no risk of trophoblastic proliferative disease in PMD. The authors report a case of placental mesenchymal dysplasia at 15 weeks of gestation associated with fetal gastroschisis and high serum beta human chorionic gonadotropin (β-hCG) that mimicked molar pregnancy.

Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Background Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed. Methods We selected combined neuroendocrine differentiation in pulmonary adenocarcinoma cases with positive ALK immunostaining. Neuroendocrine differentiation was confirmed by CD56 immunohistochemical stain. Additional ALK fluorescence in situ hybridization (FISH) study and epidermal growth factor receptor (EGFR) mutation tests were also performed. Results All four cases were positive for ALK immunohistochemistry and no EGFR mutations were detected. Interestingly, the results of ALK FISH assays showed rearrangement in only two cases. Three cases showed combined adenocarcinoma and neuroendocrine component without history of ALK-TKI administration; one of them was treated with crizotinib and experienced partial tumor regression. The remaining case had an adenocarcinoma at initial biopsy and she showed a partial response to crizotinib, and neuroendocrine changes were visible on second biopsy. Then she was treated with ceritinib and achieved a partial response. Conclusion We suggest that ALK-rearranged adenocarcinoma with combined neuroendocrine component is responsive to ALK-TKIs. Moreover, even after neuroendocrine transformation as a result of resistance to ALK-TKIs, the tumor may have partial response to second generation ALK-TKIs., Graphical Abstract

Purpose Accurate testing for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is essential for breast cancer treatment. At present, immunohistochemistry (IHC)/florescence in situ hybridization (FISH) are widely accepted as the standard testing methods. To investigate the value of NanoString nCounter®, we performed its comparative analysis with IHC/FISH and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for the assessment of ER, PR, and HER2. Methods Data on IHC/FISH results for ER, PR, and HER2 in 240 patients from a single tertiary hospital in Korea were collected and compared with NanoString nCounter® and qRT-PCR results at a single institution. Results Expression levels for each gene using NanoString nCounter® showed good correlation with the corresponding data for protein expression by IHC (p

The Ki-67 labeling index (LI) is an important prognostic factor in breast carcinoma. The Ki-67 LI is traditionally calculated via unaided microscopic estimation; however, inter-observer and intra-observer variability and low reproducibility are problems with this visual assessment (VA) method. For more accurate assessment and better reproducibility with Ki-67 LI, digital image analysis was introduced recently. We used both VA and automated digital image analysis (ADIA) (Ventana Virtuoso image management software) to estimate Ki-67 LI for 997 cases of breast carcinoma, and compared VA and ADIA results. VA and ADIA were highly correlated (intraclass correlation coefficient 0.982, and Spearman’s correlation coefficient 0.966, p

Intestinal metaplasia (IM), a premalignant lesion, is associated with an increased risk of gastric cancer. Although estrogen exposure, including tamoxifen, has been studied in correlation with gastric cancer, little has been investigated about its effects on IM.Therefore, we investigated whether chronic tamoxifen use was associated with the risk of IM in human stomach.We evaluated 512 gastric biopsies from 433 female breast cancer patients that underwent endoscopic gastroduodenoscopy (EGD) ≥6 months after breast surgery. Histopathological findings were scored according to the updated Sydney classification. Demographic and clinical characteristics were also included to identify predictive factors for IM.In a multivariate logistic regression analysis, age at EGD (odds ratio [OR], 1.04; P = 0.002), biopsies from antrum (OR 2.08; P0.001), and Helicobacter pylori positivity (OR 1.68; P = 0.016) were significantly associated with an increased risk of IM, whereas chronic tamoxifen use (≥3 months) was associated with a decreased risk of IM (OR 0.59; P = 0.025). After stratifying by biopsy site, association between tamoxifen use and IM persisted for corpus (OR 0.42; P = 0.026) but not for antrum (OR 0.74; P = 0.327). In analysis limited to patients with follow-up EGD, chronic tamoxifen use also correlated with improved IM score compared to no tamoxifen use (improved, 77.8 vs. 22.2%; no change, 65.4 vs. 34.6%; worsened, 30.0 vs. 70.0%; P = 0.019).This study suggests that chronic tamoxifen use can decrease the risk of IM in human stomach. The effect of tamoxifen is predominantly observed in the corpus.

Background Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC. Methods We investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC. Results Cytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade III (P=0.038), and higher BCLC stage (P Conclusions Notch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease-specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease-specific survival.

The majority of previous studies on pulmonary carcinoid tumor have usually focused on clinical behavior or outcome, seldom considering histopathologic features. We retrospectively collected 63 cases of resected pulmonary carcinoid tumors from 1995 to 2011 at Samsung Medical Center, Seoul, Korea. The clinical and pathological features were correlated and survival analyses were performed. Forty cases (63.5%) were classified as typical carcinoid (TC) and 23 cases (36.5%) were classified as atypical carcinoid (AC) according to WHO classification criteria. AC patients showed a higher frequency of current smoking status and a higher stage of the tumor by the American Joint Committee on Cancer than TC patients. The disease was associated with death and recurrence in five and seven patients, respectively, with almost all of the associations found in AC patients. The five-year survival rate of TC and AC were 100% and 83.5%, respectively, with AC showing poorer prognosis than TC in overall survival (OS) and disease free survival (DFS) (p=0.005 and p=0.002). Lung parenchymal invasion was observed more commonly in AC than in TC (39.1% vs 12.5%, p=0.01) and was a poor prognostic factor in OS and DFS. Rosette-like arrangements were found only in six cases of AC, while abundant basophilic cytoplasm mimicking paraganglioma and ossification were found only in TC. Through the comprehensive study of pulmonary carcinoid tumor in Korea, we suggest that lung parenchymal invasion could be a useful histologic feature to suspect the diagnosis of AC in daily practice as well as to predict the prognosis of carcinoid tumor.

Background/Aims: The prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rateof recurrence. Thus, it is crucial to identify patients with a high risk of recurrence after curative hepatectomy and to develop more effective and targeted treatment strategies to improve disease outcomes. In this study, we investigated the roles of metadherin (MTDH) in the prognosis of HCC. Methods: We investigated MTDH expression using immunohistochemistry in tumor tissue microarrays of 288 primary HCC patients who underwent curative surgical resection. Results: High MTDH expression was observed in 138 of the 288 HCC cases (47.9%). High MTDH expression was associated with a younger age (p

PURPOSE Accurate testing for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is essential for breast cancer treatment. At present, immunohistochemistry (IHC)/florescence in situ hybridization (FISH) are widely accepted as the standard testing methods. To investigate the value of NanoString nCounter®, we performed its comparative analysis with IHC/FISH and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for the assessment of ER, PR, and HER2. METHODS Data on IHC/FISH results for ER, PR, and HER2 in 240 patients from a single tertiary hospital in Korea were collected and compared with NanoString nCounter® and qRT-PCR results at a single institution. RESULTS Expression levels for each gene using NanoString nCounter® showed good correlation with the corresponding data for protein expression by IHC (p

BACKGROUND The “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS) category in the Bethesda System for Reporting Thyroid Cytopathology is a heterogeneous category of cases that are not clearly benign or malignant. METHODS We conducted an analysis of cytologic and histologic evaluations of thyroid nodules that had been interpreted as AUS/FLUS on fine-needle aspiration (FNA) at a single institution from April 2011 to April 2012. Those cases were classified into 2 subgroups according to the predominance of nuclear atypia (AUS) or microfollicular architecture (FLUS). In addition, for a number of these cases, BRAF gene mutation analyses were performed. RESULTS Of 6402 thyroid FNAs performed, 431 cases were diagnosed as AUS and 120 as FLUS. Follow-up cytologic or histologic outcome data were available for 315 AUS cases and 73 FLUS cases. Among AUS cases, 52.7% were malignant on repeat FNA or histologic diagnosis. In contrast, for FLUS, 6.8% were malignant on repeat FNA or histologic diagnosis. Among AUS/FLUS cases, 147 had adequate BRAF mutation analysis, which accompanied the histologic diagnosis. BRAF mutations were found in 87 AUS cases, 86 of which were papillary carcinoma. In contrast, there was only 1 case of BRAF mutation in FLUS. Correlating molecular results with histologic outcome revealed a 98.9% cancer probability for AUS cases with BRAF mutation. CONCLUSIONS The AUS subcategory indicates a higher risk of malignancy than the FLUS subcategory. Furthermore, BRAF molecular testing is helpful in stratifying the malignant risk of AUS cases into high-risk and low-risk groups. Cancer (Cancer Cytopathol) 2014;122:368–376. © 2014 American Cancer Society.

Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC.We investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC.Cytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade III (P=0.038), and higher BCLC stage (P0.001) were independent predictors of shorter disease-free survival. Cytoplasmic Notch3 expression tended to be an independent predictor of shorter disease-free survival (P=0.055). Notch1 expression (P=0.039), Notch4 overexpression (P=0.012), and higher BCLC stage (P0.001) were independent predictors of shorter disease-specific survival. On univariate analysis, Notch1 expression tended to show an unfavorable influence on disease-specific survival (P=0.063) and Notch4 overexpression did not show an unfavorable influence on disease-specific survival (P=0.103).Notch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease-specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease-specific survival.

Hepatocellular carcinoma (HCC) has a poor prognosis and surgical resection improves the survival rates for patients. However, the prognosis after surgical resection of HCC remains grave because of a high rate of recurrence.1,2 It is critical to determine which individual patients need adjuvant therapy in order to prevent tumor recurrence after surgical resection. Although there are many reports on histologic parameters for predicting HCC prognosis, molecular markers for HCC recurrence and prognosis could provide additional information.3 BCL9 was identified as a gene overexpressed in a precursor-B-cell acute lymphoblastic leukemia cell line with t(1;14)(q21;q32) translocation4 and it is involved in the Wnt/β-catenin signaling pathway by mediating the recruitment of pygopus to the nuclear β-catenin-TCF complex.5 Upregulation of the Wnt/β-catenin signaling pathway appears to play an important role in the development or progression of certain cancers, including colorectal cancer and HCC.6 Deregulated expression of β-catenin leads to the stabilization of β-catenin and the stabilized β-catenin translocates into the nucleus, where it can serve as a transcriptional factor through binding with the TCF transcriptional factor.7 BCL9 enhances the β-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases the cell proliferation, migration, invasion, and metastatic potential of tumor cells, while knocking down BCL9 increases the survival outcomes among xenograft mouse models of multiple myeloma and colon cancer.8 Brembeck et al.9 reported that the highly up-regulated BCL9-2 protein was found in almost all of the human colorectal carcinomas, independently of the occurrence of metastasis. A copy number gain on 1q is frequently observed in HCCs.10,11 The BCL9 gene is located at chromosome 1q21 and the regional chromosomal gain represents a primary mechanism in the activation of protooncogenes during HCC progression.12 However, the prognostic significance of BCL9 in HCC remains uncertain. In the present study, we evaluated BCL9 protein expression by immunohistochemistry in order to elucidate the prognostic significance of BCL9 in HCC patients with long-term follow-up and extensive information on the clinicopathologic characteristics.

Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients. By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months. FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (P

Preoperative differentiation between high-grade malignancy and others (benign or low-grade tumors) is more important than differentiation between malignant and benign tumors for surgical planning, treatment outcome, and prognosis in salivary gland tumors. Fine needle aspiration cytology (FNAC) has a relatively low sensitivity for differentiating malignant from benign salivary tumors. However, the diagnostic performance of FNAC has not been studied in predicting high-grade salivary malignancy, which can significantly affect patient care.Experienced cytopathologists reevaluated the adequate FNAC on 521 salivary gland tumors. The diagnostic performances of FNAC for total malignancy and high-grade malignancy were calculated, and the results were validated in independent 105 cases. In cases of high-grade cancer on FNAC, we recorded the additional diagnostic procedures and the change of surgical extent to decide how FNAC impacts clinical practice.The sensitivity, specificity, and diagnostic accuracy of FNAC in differentiating malignant from benign tumors were 64.2 % (95 % confidence interval 52.3-75.0), 98.4 % (96.5-99.3), and 92.1 % (89.1-94.6). Meanwhile, FNAC predicted high-grade malignancy accurately (94.6 % [80.0-99.5], 99.2 % [97.8-99.7], 98.9 % [97.3-99.6], respectively), a finding reproduced with similar results in the validation set. FNAC indicative of high-grade malignancy added additional imaging assessments in 94.9 %, frozen biopsy samples during surgery (tumor and lymph nodes) in 71.2 %, and changed the extent of surgery in 59.0 %.FNAC has an excellent diagnostic performance in discriminating high-grade salivary cancer, which guides clinical decision and surgical planning in salivary gland tumors.

The transforming growth factor-β/Smads signaling pathway plays an important role in tumorigenesis and progression in cancer, and may closely be related to the biological behaviors of some malignant tumors, such as gastric carcinoma. In this study, we investigated the roles of Smad3 and Smad3 phosphoisoforms in the prognosis of gastric carcinoma. We investigated the expressions of Smad3, pSmad3C(S423/425), pSmad3L(T179), pSmad3L(S204), and pSmad3L(S213) in tumor tissue microarrays of 442 gastric carcinoma patients who underwent curative surgery using immunohistochemistry and assessed their correlation with clinical outcome. Positive Smad3 expression was observed in 33.5 % of gastric carcinoma. The rates of positive Smad3 phosphoisoforms expression varied according to the location of phosphorylation within Smad3: pSmad3C(S423/425) 28.5 %, pSmad3L(T179) 5.9 %, pSmad3L(S204) 1.8 %, and pSmad3L(S213) 20.8 %. Positive Smad3 expression was associated with diffuse type (p = 0.003), poorer histologic differentiation (p = 0.005), more frequent lymph node metastasis (p = 0.001), and higher AJCC stage (p = 0.006). Multivariate analyses revealed that Smad3 expression (p = 0.041), pSmad3L(T179) expression (p = 0.011), pSmad3L(S213) expression (p = 0.003), and American Joint Committee on Cancer (AJCC) stage were independent predictors of shorter disease-free survival. Smad3 expression (p = 0.033), pSmad3L(T179) expression (p = 0.012), pSmad3L(S213) expression (p = 0.005), and AJCC stage were also independent predictors of shorter overall survival. pSmad3C(S423/425) expression tended to show favorable influences on both disease-free survival (p = 0.134) and overall survival (p = 0.232). Smad3, pSmad3L(T179), and pSmad3L(S213) expression might be independent predictors of both shorter disease-free survival and shorter overall survival in gastric carcinoma patients after curative surgery, and might help clinicians identify patients at high risk of recurrence.

C-kit-negative gastrointestinal stromal tumors (GISTs) are uncommon, and there have been few reports about the diagnosis and treatment of c-kit-negative GISTs in the stomach. We report the case of a patient who was diagnosed with a huge and atypical GIST in the stomach. The GIST was completely resected and finally diagnosed as c-kit-negative GIST based on immunohistochemical staining of tumor cells, which were negative for CD117 and CD34 and positive for Discovered on GIST-1 (DOG1). C-kit-negative GISTs could be treated by complete resection and/or imatinib, which is the same treatment for c-kit-positive GISTs.

Background: The gene for chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) was recently identified as a target oncogene within the 1q21 amplicon, which occurs in 46% to 86% of primary hepatocellular carcinoma (HCC) cases. However, the prognostic significance of CHD1L in HCC remains uncertain. In this study, we investigated the roles of CHD1L in the prognosis of HCC. Methods: We investigated the expressions of CHD1L in tumor tissue microarrays of 281 primary HCC patients who underwent surgical resection using immunohistochemistry. Prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 75.6 months. Results: CHD1L expression was observed in 48 of the 281 HCCs (17.1%). CHD1L expression was associated with a younger age (p= 0.033), higher Edmondson grade (p = 0.019), microvascular invasion (p < 0.001), major portal vein invasion (p = 0.037), higher American Joint Committee on Cancer T stage (p= 0.001), lower albumin level (p= 0.047), and higher α-fetoprotein level (p= 0.002). Multivariate analyses revealed that CHD1L expression (p= 0.027), Edmondson grade III (p= 0.034), and higher Barcelona Clinic Liver Cancer stage (p< 0.001) were independent predictors of shorter disease-free survival. Conclusions: CHD1L expression might be a prognostic marker of shorter disease-free survival in HCC patients after surgical resection.

We report a case of cardiac lymphoma in a 40-year-old man, who had a mediastinal mass which was diagnosed as sclerosing mediastinitis pathologically. The mediastinal mass caused right pulmonary arterial stenosis. The patient developed myocardial hypertrophy and echocardiography showed restrictive physiology and severely decreased left ventricle ejection fraction, 6 months later. MRI showed global left ventricular myocardial hypertrophy and diffuse late gadolinium hyperenhancement after administration of contrast material. Thus, non-ischemic cardiomyopathy was suspected on MRI. However, pathology confirmed the myocardial abnormality as lymphoma after myocardial biopsy. Because a basal part of the left ventricle and global subendocardial myocardium were not involved on contrast-enhanced delayed MRI, the MRI abnormalities could be differentiated from amyloidosis and other myocardial diseases. The peculiar non-mass forming diffuse hypertrophy pattern of cardiac lymphoma has not been known in the MRI literature.