Search

Objective Adenosquamous carcinoma of the pancreas (ASCP) is a rare histologic subtype of pancreatic carcinoma. The clinicopathologic characteristics and surgical outcomes of ASCP are poorly understood due to the rarity of this disease. Recently, promising clinical responses in patients with pancreatic cancer have been obtained for antibodies against programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). This study investigated the prevalence of PD-L1 expression and surgical outcomes of 56 ASCPs compared to 100 pancreatic ductal adenocarcinomas (PDACs). Methods A total of 56 resected cases of ASCPs were retrospectively reviewed; after matching for the T category, 100 PDACs were selected as a control group for comparison. Immunohistochemistry for p53, Smad4, and PD-L1 was performed in both groups. Results The ASCPs exhibited distinct clinicopathologic features, such as larger tumour, location in the distal pancreas, frequent vascular invasion and distant metastasis. In survival analysis, 1-and 2-year overall survival (OS) rates were 51.8% and 17.9%, respectively, with a median follow-up 13 months. According to multivariate analysis, vascular invasion and T category remained independent predictors of OS. Patients with ASCPs showed poorer survival than patients with PDACs after matching for the T category (p = 0.03). p53 and Smad4 were aberrantly expressed in 42 (75%) and 28 (50%) cases, respectively. Under the condition of a 10% cut-off value for PD-L1 positivity, approximately 11% of ASCPs were positive for PD-L1. Conclusions Approximately 11% of patients with ASCPs are assumed to be potential candidates for the application of antibodies against PD-1/PD-L1, as based on the immunohistochemical results for PD-L1.

Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors. Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes. Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01–1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features (‘AMC-C4’) was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype. We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.

Early diagnosis of hepatocellular carcinoma (HCC) increases the chances of curative treatment and long-term survival.1 2 We read with interest the analytical study by Zhang et al presenting nomogram models predicting recurrence-free survival and guiding therapeutic decisions in a patient-tailored approach to treatment of early-stage HCC within Milan criteria.3 The refined Barcelona Clinic Liver Cancer (BCLC) guidelines no longer limit the size of solitary nodules in the definition of stage A HCC. However, there is continuing debate about the need to restrict the maximum diameter of single HCCs to inside the Milan limit (≤5 cm).4–6 In a survival-based confirmatory investigation, we primarily used a Korean nationwide cancer registry database of 10 510 new HCC cases. These cases were randomly sampled and registered in 54 hospitals, and investigated by the Korea Liver Cancer Study Group and the governmental organisation of the Korea Central Cancer Registry in 2008–2014. We included in the final analysis 1610 asymptomatic HCC subjects with BCLC stage A or stage B who had preserved liver function levels referred to as Child-Pugh class A without ascites and who initially received standard treatments as per BCLC stage (online supplemental figure S1).4 The population was divided into four groups: group 1, stage A disease fulfilling Milan criteria undergoing liver resection or transplantation, or local ablation; group 2, potential stage A with single nodules >5 cm undergoing resection; group 3, potential stage B with single nodules >5 cm undergoing transarterial chemoembolisation (TACE); and group 4, stage B undergoing TACE. Five-year overall survival (OS) rates were significantly different across the four groups (p

Neuroendocrine carcinoma (NEC) is an aggressive malignant tumor that rarely arises from the gallbladder. Here, we investigated the clinicopathologic and immunohistochemical characteristics of 34 NECs of the gallbladder. The patients were predominantly women (68%) with a median age of 63 years (range, 37 to 82 y). NECs frequently occurred in the fundus (44%) as mass-forming lesions (66%). Histologically, 17 tumors were of small cell type, and another 17 were of large cell type. Twenty-three cases (68%) were associated with biliary intraepithelial neoplasia (38%) and intracholecystic papillary neoplasm (29%). The majority of tumors exhibited a diffuse growth pattern (74%), followed by organoid (24%) or scirrhous (2%) growth patterns. Histologic features related to neuroendocrine differentiation, such as nuclear molding (56%), perilobular pseudopalisading (18%), and rosette formation (15%), were identified. Immunohistochemically, cytokeratin 7 and 20 were expressed in 19 (56%) and 8 (24%) cases, respectively. Loss of Rb1 expression and concomitant overexpression of p16 were observed in 25 (74%) cases. No BRAF mutations were identified in any of the 34 NECs. For survival analysis, the 1-, 3-, and 5-year overall survival rates were 64%, 35%, and 19%, respectively. In a multivariate analysis, the receipt of adjuvant chemoradiation therapy was identified as the only independent prognostic factor associated with the overall survival rate. The 1- and 3-year overall survival rates of patients with NECs were poorer for patients with poorly differentiated adenocarcinoma of the gallbladder (P

Immunoprofiling has an established impact on the prognosis of several cancers, however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420–0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.

Matrix metalloproteinase 11 (MMP11), a member of the MMP family involved in the degradation of the extracellular matrix, has been implicated in cancer progression. Despite the stromal expression of MMP11 in breast cancer, the prognostic significance and role of MMP11 in immune or stromal cells of breast cancer remain unclear. Based on the immunohistochemical analysis of breast cancer tissues from 497 patients, we demonstrated that MMP11 expression in mononuclear inflammatory cells (predominantly macrophages) is an independent negative prognostic factor in breast cancer, whereas MMP11 expression in tumor cells and fibroblasts is not associated with patient survival. Enforced MMP11 expression in breast cancer cells did not promote cell proliferation and migration. However, MMP11-overexpressing macrophages enhanced the migration of HER2-positive (HER2+) breast cancer cells, recruitment of monocytes, and tube formation of endothelial cells. Furthermore, we found that the chemokine CCL2 secreted from MMP11-overexpressing macrophages activated the MAPK pathway via its receptor CCR2 in breast cancer cells, thereby promoting the migration of HER2+ breast cancer cells through MMP9 upregulation. We also found that MMP11 expression in macrophages was stimulated by MMP11-overepressing HER2+ breast cancer cells. Collectively, our findings provide evidence that MMP11 in macrophages may play a pro-tumoral role in HER2+ breast cancer through interaction with cancer cells, monocytes, and endothelial cells.

The administration of mesenchymal stem cells (MSCs) was shown to attenuate overt as well as early diabetic nephropathy in rodents, but the underlying mechanism of this beneficial effect is largely unknown. Inflammation and mitochondrial dysfunction are major pathogenic factors in diabetic nephropathy. In this study, we found that the repeated administration of MSCs prevents albuminuria and injury to tubular epithelial cells (TECs), an important element in the progression of diabetic nephropathy, by improving mitochondrial function. The expression of M1 macrophage markers was significantly increased in diabetic kidneys compared with that in control kidneys. Interestingly, the expression of arginase-1 (Arg1), an important M2 macrophage marker, was reduced in diabetic kidneys and increased by MSC treatment. In cultured TECs, conditioned media from lipopolysaccharide-activated macrophages reduced peroxisomal proliferator-activated receptor gamma coactivator 1α (Pgc1a) expression and impaired mitochondrial function. The coculture of macrophages with MSCs increased and decreased the expression of Arg1 and M1 markers, respectively. Treatment with conditioned media from cocultured macrophages prevented activated macrophage-induced mitochondrial dysfunction in TECs. In the absence of MSC coculture, Arg1 overexpression in macrophages reversed Pgc1a suppression in TECs. These observations suggest that MSCs prevent the progression of diabetic nephropathy by reversing mitochondrial dysfunction in TECs via the induction of Arg1 in macrophages., Kidney disease: stem cells to the rescue Stem cells can halt the progression of kidney damage owing to diabetes by reducing inflammation and improving energy production in kidney cells. Eun Hee Koh at the University of Ulsan College of Medicine in Seoul, South Korea, and colleagues found that adult stem cells, known as mesenchymal stem cells (MSCs), derived from human umbilical cord blood had a protective effect on the kidneys of diabetic mice. Repeated administration of MSCs prevented the recruitment of pro-inflammatory cells into the kidney and increased the levels of arginase-1, a marker of cells with anti-inflammatory activity. Experiments in cells showed that MSCs stimulated the production of arginase-1 in that, in turn, were able to increase the production and activity of mitochondria in kidney cells. This study confirms an important role for MSCs in organ repair.

Background Breast cancer treatment with selective estrogen receptor modulators (SERMs) increases the incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologic characteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discuss possible pathogenetic mechanisms. Methods Among 28,104 patients with breast cancer, clinicopathologic features and incidence of uMMMT were compared between patients who underwent SERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period, incidence, dose, and duration of SERM treatment, as well as overall survival rate, were compared for patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMT vs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathological findings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ, progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT. Results The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold). All patients with SERM were postmenopausal and received daily 20–40 mg SERM. Cumulative SERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologic features, such as International Federation of Gynecology and Obstetrics stage and overall survival, were not significantly different between patients with S-uMMMT and NS-uMMMT or between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available for immunostaining exhibited strong overexpression/null expression of p53 protein and significantly increased ERβ expression in carcinomatous and sarcomatous components. Conclusions SERM therapy seemingly increases risk of S-uMMMT development; however, clinicopathologic features were similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expression might be involved in the etiology of S-uMMMT.

Microfluidic devices as translational research tools provide a potential alternative to animal experiments due to their ability to mimic physiological parameters. Several approaches that can be used to predict the efficacy or toxicity of anticancer drugs are available. In general, standard cell culture systems have the advantages of being relatively cost-effective, having high-throughput capability, and providing convenience. However, these models are inadequate to accurately recapitulate the complex organ-level physiological and pharmacological responses. Here, we present a one-stop microfluidic device enabling both 3-dimensional (3D) lung cancer organoid culturing and drug sensitivity tests directly on a microphysiological system (MPS). Our platform reproducibly yields 3D lung cancer organoids in a size-controllable manner and demonstrates for the first time the production of lung cancer organoids from patients with small-cell lung cancer. Lung cancer organoids derived from primary small-cell lung cancer tumors can rapidly proliferate and exhibit disease-specific characteristics in our MPS. Cisplatin and etoposide, the standard regimen for lung cancer, showed increased apoptosis induction in a concentration-dependent manner, but the organoids contained chemo-resistant cells in the core. We envision that this system may provide important information to guide therapeutic approaches at the preclinical level.

BACKGROUND AND AIMS Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown. METHODS To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC. RESULTS Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). This study aimed to investigate clinicopathologic characteristics of colorectal NECs and elucidate genomic differences and similarities between colorectal NECs and colorectal adenocarcinomas (ACs). A total of 30 colorectal NECs were screened for frequently identified CRC oncogenic driver genes by targeted next-generation sequencing of 382 genes. The median age of the patients was 67 years (range, 44 to 88 years). NECs occurred predominantly in the rectum (47%) and exhibited multiple adverse prognostic pathologic factors, including frequent lymphatic and vascular invasions, high rates of lymph node metastasis and distant metastasis and advanced TNM stage. The 1-, 3-, and 5-year overall survival rates of NEC patients were 46.7%, 36.4%, and 32.7%, respectively, with a median overall survival period of 11.5 months. In a molecular analysis, NECs showed high rates of BRAF mutation (23%), predominantly p.V600E (71%), and alterations in RB1 (47%), particularly deletion (57%). The frequencies and distributions of other genes, such as KRAS, APC, SMAD4, and PIK3CA, and microsatellite instability status were similar to those of ACs. These findings provide beneficial information for selecting therapeutic options, including targeted therapy, and a better understanding of the histogenesis of this tumour.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

Ependymomas are biologically and clinically heterogeneous tumors of the central nervous system that have variable clinical outcomes. The status of the tumor immune microenvironment in ependymoma remains unclear. Immune cell subsets and programmed death ligand 1 (PD-L1) expression were measured in 178 classical ependymoma cases by immunohistochemistry using monoclonal antibodies that recognized tumor-infiltrating lymphocyte subsets (TILs; CD3, CD4, CD8, FOXP3, and CD20), tumor-associated macrophages (TAMs; CD68, CD163, AIF1), indoleamine 2,3-dioxygenase (IDO)+ cells and PD-L1-expressing tumor cells. Increases in CD3+ and CD8+ cell numbers were associated with a prolonged PFS. In contrast, increased numbers of FOXP3+ and CD68+ cells and a ratio of CD163/AIF1+ cells were significantly associated with a shorter PFS. An increase in the IDO+ cell number was associated with a significantly longer PFS. To consider the quantities of TILs, TAMs, and IDO+ cells together, the cases were clustered into 2 immune cell subgroups using a k-means clustering analysis. Immune cell subgroup A, which was defined by high CD3+, low CD68+ and high IDO+ cell counts, predicted a favorable PFS compared to subgroup B by univariate and multivariate analyses. We found six ependymoma cases expressing PD-L1. All these cases were supratentorial ependymoma, RELA fusion-positive (ST-RELA). PD-L1 expression showed no prognostic significance. This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments.

Next-generation sequencing (NGS) has recently emerged as an essential component of personalized cancer medicine due to its high throughput and low per-base cost. However, no sufficient guidelines for implementing NGS as a clinical molecular pathology test are established in Korea. To ensure clinical grade quality without inhibiting adoption of NGS, a taskforce team assembled by the Korean Society of Pathologists developed laboratory guidelines for NGS cancer panel testing procedures and requirements for clinical implementation of NGS. This consensus standard proposal consists of two parts: laboratory guidelines and requirements for clinical NGS laboratories. The laboratory guidelines part addressed several important issues across multistep NGS cancer panel tests including choice of gene panel and platform, sample handling, nucleic acid management, sample identity tracking, library preparation, sequencing, analysis and reporting. Requirements for clinical NGS tests were summarized in terms of documentation, validation, quality management, and other required written policies. Together with appropriate pathologist training and international laboratory standards, these laboratory standards would help molecular pathology laboratories to successfully implement NGS cancer panel tests in clinic. In this way, the oncology community would be able to help patients to benefit more from personalized cancer medicine.

// Hyo Jeong Kang 1, * , Dal-Hee Chung 1, 2, * , Chang Ohk Sung 1 , Su Hyun Yoo 1 , Eunsil Yu 1 , Nayoung Kim 2 , Sy-Hye Lee 2 , Ji-Young Song 2 , Chong Jai Kim 1 , Jene Choi 1 1 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Asan Institute for Life Science, Asan Medical Center, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Jene Choi, email: jenec@amc.seoul.kr Keywords: SHP2, NF-κB, hepatitis B virus, cirrhosis, hepatocellular carcinoma Received: March 18, 2016 Accepted: February 20, 2017 Published: March 06, 2017 ABSTRACT The non-receptor tyrosine phosphatase SHP2 has scaffolding functions in signal transduction cascades downstream of growth receptors. A recent study suggested that SHP2 acts as a tumor suppressor during hepatocellular carcinoma (HCC) development. Herein we examined whether SHP2 links the HBx–NF-κB pathway to EGFR signaling during HCC development. The overexpression of HBx or NF-κB led to increased SHP2 expression via NF-κB binding to the Shp2 promoter. EGF treatment induced ERK activation as well as the rapid assembly of SHP2, EGFR, and Gab1. Upon LPS stimulation, NF-κB–SHP2–ERK activation and phosphorylated STAT3 levels exhibited a negative correlation in vitro . By contrast, in patients with HBV-associated HCC, NF-κB–SHP2–ERK and IL-6–JAK–STAT3 pathway activity levels were concomitantly higher in adjacent non-neoplastic tissues than in HCC tissues. The immunohistochemical analysis of 162 tissues of patients with HCC revealed that SHP2 levels were significantly higher in non-neoplastic background tissues than in corresponding HCC tissues and considerably increased in background liver tissues with advanced fibrosis ( P < 0.001). SHP2 expression increased gradually from normal liver to chronic hepatitis, cirrhosis, and background liver with a dysplastic nodule, but was decreased or lost in dysplastic nodules and HCC. This is the first report to describe the existence of the HBx–NF-κB–SHP2 pathway, linking HBV infection to the EGFR–RAS–RAF–MAPK pathway in the liver. SHP2 depletion from the negative crosstalk between NF-κB and STAT3 accelerates HCC development.

Objective Genomic characteristics of gestational trophoblastic neoplasm (GTN) are mostly unknown. This study reveals the molecular features of malignant GTN, including choriocarcinoma (CC), epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT), by whole transcriptome sequencing analysis. Methods Data obtained from the total RNA sequencing of 2 CC, 4 ETT, and 4 PSTT were evaluated for differential gene expression, pathway alteration, fusion gene, infiltrating immune cell type, PD-L1 and PTEN expression level, and mutation analysis was performed. Results The transcriptome data were correlated with known biomarkers, including HDS3B1, p63, hCG, and hPL for all tumor types. ETT and PSTT were more closely clustered compared with CC in clustering analysis using gene expression; however, ETT showed various altered signaling pathways, including PI3K-Akt-mTOR, with frequent loss of PTEN protein expression. This finding was both well correlated with PIK3CA c.3140A > G pathogenic mutation, detected in 1 ETT, and further confirmed using the MassARRAY method. PSTT showed an overexpressed gene cluster associated with muscle contraction and G protein-coupled receptor activity. No significant fusion gene was seen in all 10 cases. In tumor-infiltrating immune cell profiles, CD4 memory T cell and macrophage signature were relatively high in ETT and PSTT. PD-L1 mRNA expression level was high in all cases, which was significantly correlated with the PD-L1 level by immunohistochemistry (p = 0.03) with positivity in all 10 cases. Conclusions ETT and PSTT were similar at the transcriptome level, with a high level of PD-L1 expression in all tumor types; however, specific pathways, such as PI3K signaling, were altered in ETT.

The immunogenomic characteristics of hepatocellular carcinomas (HCCs) with immune cell stroma (HCC-IS), defined histologically, have not been clarified. We investigated the clinical and molecular features of HCC-IS and the prognostic impact of Epstein-Barr virus (EBV) infection.We evaluated 219 patients with conventional HCC (C-HCC) and 47 with HCC-IS using in situ hybridization for EBV, immunohistochemistry, multiplex immunofluorescence staining, and whole exome and transcriptome sequencing. Human leukocyte antigen types were also extracted from the sequencing data. Genomic and prognostic parameters were compared between HCC-IS and C-HCC.CD8 T cell infiltration was more frequent in HCC-IS than C-HCC (mean fraction/sample, 22.6% vs. 8.9%, false discovery rate q 0.001), as was EBV positivity in CD20-positive tumor-infiltrating lymphocytes (TILs) (74.5% vs. 4.6%, p 0.001). CTNNB1 mutations were not identified in any HCC-IS, while they were present in 24.1% of C-HCC (p = 0.016). Inhibitory and stimulatory immune modulators were expressed at similar levels in HCC-IS and EBV-positive C-HCC. Global hypermethylation, and expression of PD-1 and PD-L1 in TILs, and PD-L1 in tumors, were also associated with HCC-IS (p 0.001), whereas human leukocyte antigen type did not differ according to HCC type or EBV positivity. HCC-IS was an independent factor for favorable recurrence-free survival (adjusted hazard ratio [aHR] 0.23; p = 0.002). However, a subgroup of tumors with a high density of EBV-positive TILs had poorer recurrence-free (aHR 25.48; p 0.001) and overall (aHR 9.6; p = 0.003) survival, and significant enrichment of CD8 T cell exhaustion signatures (q = 0.0296).HCC-IS is a distinct HCC subtype associated with a good prognosis and frequent EBV-positive TILs. However, paradoxically, a high density of EBV-positive TILs in tumors is associated with inferior prognostic outcomes. Patients with HCC-IS could be candidates for immunotherapy.Hepatocellular carcinomas with histologic evidence of abundant immune cell infiltration are characterized by frequent activation of Epstein-Barr virus in tumor-infiltrating lymphocytes and less aggressive clinical behavior. However, a high density of Epstein-Barr virus-positive tumor-infiltrating lymphocytes is associated with inferior prognostic outcomes, possibly as a result of immune escape due to significant CD8 T cell exhaustion.

Molecular testing is increasingly important in cancer diagnosis. Targeted next generation sequencing (NGS) is widely accepted method but structural variation (SV) detection by targeted NGS remains challenging. In the brain tumor, identification of molecular alterations, including 1p/19q co-deletion, is essential for accurate glial tumor classification. Hence, we used targeted NGS to detect 1p/19q co-deletion using a newly developed deep learning (DL) model in 61 tumors, including 19 oligodendroglial tumors. An ensemble 1-dimentional convolution neural network was developed and used to detect the 1p/19q co-deletion. External validation was performed using 427 low-grade glial tumors from The Cancer Genome Atlas (TCGA). Manual review of the copy number plot from the targeted NGS identified the 1p/19q co-deletion in all 19 oligodendroglial tumors. Our DL model also perfectly detected the 1p/19q co-deletion (area under the curve, AUC = 1) in the testing set, and yielded reproducible results (AUC = 0.9652) in the validation set (n = 427), although the validation data were generated on a completely different platform (SNP Array 6.0 platform). In conclusion, targeted NGS using a cancer gene panel is a promising approach for classifying glial tumors, and DL can be successfully integrated for the SV detection in NGS data.

In recent decades, fine needle aspiration cytology (FNAC) has been established as an efficient diagnostic tool for superficial masses, including salivary gland lesions. FNAC is technically simple, safe, fast, and cost-effective. However, FNAC traditionally demonstrates relatively low sensitivity in comparison with its high specificity for diagnosing salivary gland tumors. According to a previous meta-analysis by Schmidt et al. [1], the average sensitivity and specificity determined in 6,169 cases were 80% and 97%, respectively. Recent studies report that the sensitivity and specificity of FNAC range between 64%–90% and 86%–100%, respectively [2-8]. The low sensitivity of FNAC can be attributed to several factors, but is primarily due to the difficulty of diagnosing low-grade carcinomas by cellular morphology alone. Core needle biopsy (CNB) is a relatively new technique for diagnosing salivary gland lesions. Since intact tissue cores can be retrieved using ultrasound-guided CNB, improved specimen adequacy is expected. The sensitivity and specificity of salivary gland CNB are reportedly 92%–94% and 99%–100%, respectively [9-12]. Preoperative evaluation of salivary gland lesions should provide the clinicians with a treatment plan including the type and extent of surgical intervention needed. For this purpose, differentiating benign from malignant tumors is crucial, and moreover, information on the grade and specific type of the tumor will further aid in the choice of therapeutic procedures. With the aim of establishing the most accurate diagnostic tool as new techniques emerge, we compared the diagnostic accuracy and accurate tumor subtyping rates of CNB and FNAC performed for the preoperative evaluation of salivary gland tumors.

Background Homeodomain-interacting protein kinase 2 (HIPK2) is responsible for a DNA damage response, centrally regulating p53. The aberrant HIPK2 expression is known to be involved in carcinogenesis in several malignancies. However, the correlation of HIPK2 expression along with progression of cutaneous epithelial neoplasm has not been investigated. Methods Using immunohistochemistry and real-time reverse transcription–polymerase chain reaction, we examined the correlation between HIPK2 and HIPK2-related protein expressions and the progression of some cutaneous epithelial neoplasms (i.e., actinic keratosis, Bowen's disease, keratoacanthoma, squamous cell carcinoma, and basal cell carcinoma). Results HIPK2 expression was distinct between preinvasive and invasive lesions: the expression decreased in keratoacanthoma (none of eight) and squamous cell carcinoma (five of 35) compared to actinic keratosis (12 of 19) and Bowen's disease (10 of 23) (P

The aim of this study was to investigate the value of [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in predicting lymph node status in node-negative endometrial cancer on preoperative magnetic resonance imaging (MRI). Patients with endometrial cancer who underwent both preoperative MRI and FDG-PET/CT followed by hysterectomy and lymphadenectomy were initially included. We then enrolled patients with MRI-defined node-negative disease (lymph nodes

Carcinosarcoma is an aggressive malignant neoplasm of the female genital tract that is biphasic and composed of carcinomatous and sarcomatous components. It was previously considered as a subtype of uterine sarcoma but is currently regarded as a type of metaplastic carcinoma. 1 Here, we report a case in which a carcinosarcoma forming a discrete mass in the peritoneal cavity was diagnosed concurrently with smaller bilateral ovarian masses showing unequivocal histologic features of high-grade serous carcinoma. Although there seems to be a close relationship between the two tumors in this case, firm evidence for the histopathologic determination of the primary site is lacking because primary carcinosarcomas have been described in many extragenital organs, including the peritoneum, in the literature. We demonstrated two tumors with different histologic findings at distant tumor locations but with a common origin in their pathogenetic mechanism, as suggested by their similar immunohistochemical overexpression of p53 protein and identical pattern TP53 mutation and microsatellites (the reference panel, the Bethesda markers) by molecular analysis.

Background BRAF mutation has received a great deal of attention in neuro-oncology field, recently. This study aimed to investigate the incidence and the clinical significance of BRAFV600E in low-grade glial tumors. Methods An institutional cohort of 105 brain tumors (51 dysembryoplastic neuroepithelial tumors (DNTs), 14 subependymal giant cell astrocytomas (SEGAs), 12 glioblastoma with neuronal marker expression (GBM-N), and 28 pleomorphic xanthoastrocytomas (PXAs)) from 100 patients were investigated for the presence of BRAFV600E by direct sequencing. Results We found frequent BRAFV600E in DNTs (26/51, 51%), SEGAs (6/14, 42.9%), and PXAs (14/28, 50%). In DNTs, BRAFV600E was more commonly detected in tumors with extra-temporal location (68.2% vs. 37.9%; P = 0.032). The diagnostic subgroups of tuberous sclerosis complex were not correlated with BRAFV600E in patients with SEGA (P = 0.533). One PXA case revealed a unique duplication mutation (p.Thr599dup) of codon 599. All GMB-N cases did not carry BRAF mutation. Conclusions Our data indicate that BRAFV600E is a common genetic alteration in low-grade glial tumors with neuronal component or differentiation. High frequency of BRAFV600E in DNTs and SEGAs would be useful in the differential diagnosis, and also offers a potential specific treatment targeting BRAFV600E. J. Surg. Oncol. 2015 111:359–364. © 2014 Wiley Periodicals, Inc.

Aims To identify histopathological and immunohistochemical findings that aid diagnosis of metastatic endometrial stromal sarcoma (ESS) in small biopsy specimens of the lung. Methods and results We reviewed the histology of 46 lung nodules from 10 cases of pulmonary metastatic ESS. Biopsy sections were analysed by immunohistochemistry to highlight blood and lymphatic vasculature, and for expression of CD10 and oestrogen receptor (ER). Various histological changes were identified that could mislead in making a diagnosis on small biopsy samples: haemangiopericytomatous blood vessels (39%), absence of characteristic spiral arteriole-like vasculature (26%), intratumoral cysts formed by dilatation of airways (22%) or intratumoral myxoid change (11%), prominent interstitial collagen deposits (48%), foam cell infiltration (4%) and smooth muscle differentiation (2%). Peribronchial/peribronchiolar distribution of tumour cells with juxtaepithelial growth was a frequent feature, observed in 59% of nodules. In two very small nodules the lesion was barely recognizable histologically; tumour cells were detected only by expression of ER and CD10. Conclusions Combined staining for ER and CD10 can be helpful in avoiding an erroneous diagnosis. As lymphatics are not normally present in the juxtaepithelial bronchial/bronchiolar wall, juxtaepithelial tumour growth beneath the bronchial epithelium in early metastatic lesions indicates a haematogenous metastastic route through the bronchial artery.

Background/Aims: To evaluate the clinical and pathologic features of patients with mucinous borderline tumor (MBT) of the ovary with special emphasis on the endocervical-like (EMBT) and intestinal-type (IMBT). Methods: This is a retrospective review of patients with MBT who were diagnosed and treated between 1995 and 2009 at a single institution. The records were analyzed for the patients' clinicopathologic information. The survival rates were calculated using the Kaplan-Meier method. Results: Of a total of 203 patients with MBT, there were 56 (27.6%) with EMBTs and 147 (72.4%) with IMBTs. Patients with EMBTs were significantly more asymptomatic (58.9%), had higher CA125 and CA19-9 levels, larger tumors (mean 17.3 cm), less frequent bilateral occurrence (5.4%), and less relation to endometriosis (1.4%), compared with those with IMBTs (all p < 0.05). During the median follow-up of 57.3 months (range 6-158), a total of 8 recurrences were identified: 6 were borderline and 2 were invasive lesion. With regard to the recurrence, EMBT and IMBT showed a 7-year recurrence-free survival rate of 97.1 and 92.1%, respectively, with no significant difference. Conclusion: EMBT and IMBT had different clinicopathological profiles, although the histologic distinction of MBT was not associated with the prognosis.

// Jin Roh 1 , Youkyoung Jeon 6 , A-Neum Lee 4, 5 , Sang Min Lee 7 , YeonMee Kim 8 , Chang Ohk Sung 1 , Chan-Jeoung Park 3 , Jung Yong Hong 2 , Dok Hyun Yoon 2 , Cheolwon Suh 2 , Jooryung Huh 1 , Inhak Choi 6, * and Chan-Sik Park 1, 4, 5, * 1 Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 2 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 3 Department of Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 4 Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 5 Cell Dysfunction Research Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 6 Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan, Korea 7 Department of Hematology/Oncology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea 8 Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea * These authors have contributed equally to this work Correspondence to: Chan-Sik Park, email: csikpark@amc.seoul.kr Inhak Choi, email: miccih@inje.ac.kr Keywords: multiple myeloma, immune checkpoint, VSIG4, immunohistochemistry, prognosis Received: November 14, 2016 Accepted: June 20, 2017 Published: July 22, 2017 ABSTRACT Multiple myeloma (MM) remains as an incurable disease, despite recent substantial improvements in treatment. Therefore, development of novel biomarkers for risk stratification and new therapeutic targets are imperative. One of the emerging treatments for MM is the immune checkpoint blockades. V-set Ig domain-containing 4 (VSIG4) is a lately studied B7-related immune checkpoint modulator. We assessed the VSIG4 expression in patients with MM and its prognostic impact. We analyzed 81 bone marrow and 66 extramedullary biopsy samples of MM patients using immunohistochemistry. VSIG4 mRNA expression data from the Multiple Myeloma Genomics Portal (MMGP) were analyzed to validate our results. The overall survival (OS) of the high VSIG4 expression group was significantly poorer than that of the low VSIG4 expression group ( p = 0.046). VSIG4 expression was remained statistically significant after adjustment for revised international staging system (rISS) and Mayo stratification algorithm (mSMART) risk classification, respectively ( p = 0.019 and 0.017). Corroborating results were also observed on analyses of VSIG4 expression in patients with extramedullary MM and external data from the MMGP. Our results suggest that VSIG4 expression in MM is an independent indicator of poor prognosis, implying a possible therapeutic target for immunotherapy for MM.

Gliomatosis peritonei (GP) is commonly associated with ovarian teratoma and is not thought to have an adverse prognostic effect. However, the prognostic impact and characteristics of GP remain to be clarified. In this study, we investigated the clinicopathologic features of ovarian teratoma associated with GP, and we further compared ovarian immature teratoma (IT) with GP to ovarian IT without GP. During the study period, there were a total of 16 ovarian teratomas associated with GP. Among them, 15 cases were ovarian ITs of various grades. When ovarian IT with GP (n = 15) was compared to ovarian IT without GP (n = 27), it was found that ovarian IT patients with GP had larger tumor size (median, 19 vs. 13 cm; P < 0.001), more frequent recurrence (40 %, 6/15 vs. 3.7 %, 1/27; P = 0.005), and frequently elevated preoperative CA-125 level (100 %, 12/12 vs. 50 %, 10/20; P = 0.004). All recurrences occurred within 2 years of the initial surgery. Survival curves indicated that ovarian IT patients with GP had significantly shorter recurrence-free survival compared to those without GP (P = 0.002). The 2-year recurrence-free survival rates were 59.3 and 96.3 % in IT with GP and IT without GP, respectively. However, all but one case of IT with GP are currently alive. In conclusion, GP is an adverse prognostic factor characterized by frequent recurrence in patients with ovarian IT.

Background Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. Methods We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. Results It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. Conclusions In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.

Background Mucinous gastric carcinoma (MGC) is a distinct histologic subtype of gastric cancer. However, the prognostic significances of the current TNM staging system and histology in MGC have not been studied. Methods 206 patients who underwent R0 resection for MGC were classified by tumor size (

Objective Higher level of circulating monocyte has been reported to be related with higher cancer incidence and mortality. We investigated the role of pre-treatment circulating monocyte count for cancer specific survival in cervical squamous cell carcinoma patients comparing with pre-treatment squamous cell carcinoma-related antigen (SCC-Ag) level. Methods We retrospectively enrolled patients with squamous cell carcinoma of the cervix (FIGO stage IB to IVA) who had complete blood cell counts with differential cell count and serum SCC-Ag level within 2weeks before starting initial treatment and were treated at Samsung Medical Center, Seoul, Korea, from 1996 to 2007. Results The 788 patients in our study group had a median follow-up of 53.4months and a five-year survival rate of 87.8%. The median value for pre-treatment circulating monocyte count was 349/μl (21–1463), and the median concentration of SCC-Ag was 1.6ng/ml (0.1–362.0). In multivariable analysis, the pre-treatment circulating monocyte count was an independent prognostic factor for progression-free survival and overall survival in locally advanced disease ( P =0.007 and P =0.038) but not in case of SCC-Ag for overall survival. The combined index of monocyte count and SCC-Ag level could enhance the prognostic value of SCC-Ag alone in patients with locally advanced cervical squamous cell carcinoma. Conclusions A higher pre-treatment circulating monocyte count is independently associated with poor prognosis in patients with locally advanced cervical squamous cell carcinoma. The pre-treatment circulating monocyte count may be considered as an adjunctive biomarker with SCC-Ag.

Pathological detection of lymphovascular space invasion (LVSI) is a useful prognostic marker for patients with endometrial cancer. However, LVSI is criticized for its subjectivity and poor reproducibility. To improve the outcomes of patients with endometrial cancer, we evaluated objective parameters associated with LVSI to generate more accurate LVSI assessments and to identify patients with high-risk disease. We reviewed the medical records of 137 patients with endometrial cancer. Flow cytometry was used to determine DNA ploidy and S-phase fraction. Estrogen and progesterone receptor (ER and PR) levels and p53 and k-ras mutational status were tested. LVSI was found in 36 patients (26.3%). Patients with LVSI had significantly decreased recurrence-free survival and overall survival compared to those without LVSI. Aneuploid tumors were significantly more frequent in LVSI-positive patients compared with LVSI-negative patients (odds ratio = 5.208, P

Galectin-3 (Gal-3) is a β-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P

Claudins are 22-27 kDa sized adhesion molecules that constitute tight junctions. Their expression levels are often tissue-specific, and their altered degrees of expression have been reported in a variety of cancers. In addition, the prognostic significance of claudin expression has been implicated in various human cancers. However, the prognostic significance of claudin-4 expression in esophageal squamous cell carcinoma (ESCC) remains to be clarified.We investigated the prognostic significance of claudin-4 expression in 164 cases of ESCC using immunohistochemisty. We also evaluated claudin-4 mRNA expression levels using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and analyzed its specific promoter methylation status using quantitative methylation-specific PCR.According to clinicopathological parameters, low claudin-4 expression was found to be significantly associated with histological differentiation (P = 0.003), invasion depth (P = 0.002), and lymph node metastasis (P = 0.024). Low claudin-4 expression showed unfavorable influences on disease-free survival (P = 0.0115) and overall survival (OS) (P = 0.0009). In multivariate analysis, low claudin-4 expression was an independent predictor of poor OS (P = 0.007). Claudin-4 mRNA levels assessed using real-time RT-PCR were consistent with the protein levels determined using immunohistochemistry. Furthermore, this study demonstrates that loss of claudin-4 is associated with promoter hypermethylation.Our study indicates that claudin-4 expression is deregulated in ESCC, implying its potential use as a prognostic biomarker in ESCC.

Background/Aims Although gastric hyperplastic polyps are usually considered as benign lesions, a low risk of carcinomatous conversion is currently recognized. We aimed to identify the characteristics of hyperplastic polyps undergoing neoplastic transformation. Methods A total of 269 gastric hyperplastic polyps from 216 patients removed by endoscopic polypectomy (EP) or surgical resection were enrolled in this study, and their endoscopic pictures and pathology slides were reviewed. Results Neoplastic transformation was detected on forceps biopsy specimen in 11 cases. However, the pathology findings from the EP or surgical specimen revealed neoplastic transformation in 14 cases (5.2%; 4 with dysplasia and 10 with adenocarcinoma). No significant difference was found between hyperplastic polyps with and without neoplastic transformation in age, sex, location, number of polyps or gross appearance. However, neoplastic transformations were more frequently found in gastric hyperplastic polyps >1 cm than in polyps ≤1 cm (12 of 143; 8.4% vs. 2 of 126; 1.6%) (p=0.013). Conclusions Neoplastic transformations were more frequently found in gastric hyperplastic polyps >1 cm. Therefore, EP should be considered for gastric hyperplastic polyps >1 cm for the accurate diagnosis and definitive treatment.

Granulocytic sarcoma is a rare extramedullary tumor composed of myeloid progenitor cells. Primary involvement of the biliary tract without evidence of leukemia is exceedingly rare. Here, we report an isolated biliary granulocytic sarcoma in a 30-yr-old man who presented with jaundice, fever, and chill without any evidence of leukemia. However, five months after the diagnosis, he developed acute myelogenous leukemia with multilineage dysplasia and chromosomal abnormality. A rare possibility of biliary granulocytic sarcoma should be considered as a differential diagnosis in patients with obstructive jaundice. A histologic evaluation by aggressive diagnostic intervention is important and may improve prognosis.

We present a case of retroperitoneal arteriovenous malformation extending through the inferior vena cava into the heart, which was associated with dissection of the inferior vena cava in a 32-year-old female. Computed tomography and magnetic resonance imaging showed a double-lumen inferior vena cava and a rod-like solid component attached to a sac-like lesion in the right heart chambers. Digital subtraction angiography showed an arteriovenous malformation draining to the inner lumen of the inferior vena cava.

Acute phase reactants are a group of hepatic proteins that are synthesized and released into the circulation in response to certain stresses such as infection and physical injury [1]. C-reactive protein (CRP) is a well-known, major acute phase reactant that was originally found in the sera of patients infected with Streptococcus pneumoniae [2,3]. CRP mRNA transcription is primarily induced by pro-inflammatory cytokines interleukin (IL)-6 and IL- 1 [4-6]. The blood concentration of CRP is increased in inflammatory conditions of both infectious and non-infectious etiologies such as urinary tract infection and hyperlipidemic acute pancreatitis [7,8]. A growing body of evidence indicates a solid pathobiological relationship between chronic inflammation and carcinogenesis [9]. Innate immune components such as Toll-like receptors and NOD-like receptors play a role in the regulation of inflammation and development of cancer [10-12]. Serum CRP level has been shown to be a prognostic marker in various human cancers [13,14]. Likewise, high serum CRP level is a poor prognostic factor in hepatocellular carcinoma (HCC) in relation to early recurrence [15,16]. As hepatocytes are the primary origin of CRP synthesis, it is highly likely that neoplastic hepatocytes retain a functional capacity to synthesize CRP under the influence of pro-inflammatory stimuli. Not surprisingly, CRP expression has been rather extensively studied in hepatocellular adenomas [17,18], and CRP immunoreactivity is a critical parameter for molecular phenotyping and defining of the inflammatory subtype of hepatocel lular adenoma, which has a higher risk of malignant transformation [19-21]. Of note, based on the results of immunohistochemistry using a panel of antibodies and fluorescence in situ hybridization for gains of chromosomes 1, 8, and MYC in HCC arising in adenoma, Kakar et al.[22] recently proposed that a certain subset of hepatocellular adenomas may represent a well-differentiated version of HCCs. However, CRP expression in HCCs has not yet been studied. We postulated that the evaluation of CRP expression in HCC may provide valuable information regarding the unique biology of HCCs. This study was conducted to determine whether CRP is produced by HCC cells and to assess its clinicopathologic significance.

Carbonic anhydrase 9 (CA9), which regulates cellular proliferation and the acid-base balance, is known as prognostic factor in various types of cancer. The aim of this study is to investigate the clinical implications of CA9 expression in patients with hepatocellular carcinoma. Immunohistochemical staining for CA9 was performed on tissue microarrays of hepatocellular carcinoma and paired non-neoplastic liver tissue from a training cohort of 838 patients and a validation cohort of 225 patients. Membranous staining in more than 5 % of the tumor cells was considered to indicate CA9 positivity. The prognostic value of CA9 expression was statistically evaluated. In the training cohort, CA9 positivity (181 cases, 21.5 %) was significantly correlated with shorter overall survival (OS; p < 0.001) and recurrence-free survival (RFS; p = 0.004). In multivariate analysis, CA9 positivity was independently associated with reduced OS (p = 0.023), but not significantly associated with RFS (p = 0.384). These results were validated in an additional cohort (CA9 positivity in 35 cases, 15.6 %; OS, p = 0.015; RFS, p = 0.979). Pooled cohort analysis showed that this predictor was independently associated with higher mortality (OS; p < 0.001). These data indicate that CA9 expression is a poor prognostic factor in resectable hepatocellular carcinoma (HCC) patients.

Malignant transformation of mature cystic teratoma is uncommon, and occurs in approximately 2%–4% of cases [1]. The most common tumor is squamous cell carcinoma, followed by mucinous carcinoma, carcinoid tumor, thyroid carcinoma, etc.; however, any of the tissues in mature teratoma may undergo malignant transformation [1]. Goblet cell carcinoid (mucinous carcinoid) is a distinctive neoplasm with features of both carcinoid tumor and adenocarcinoma. Most cases described in the literature have occurred in the appendix and rarely, in the ovary. Although mature cystic teratomas occur in many extragonadal areas including the mesentery [2] and greater omentum, occurrence of goblet cell carcinoid arising in extragonadal teratoma has been rarely described, with only a single case in mediastinum being reported in the English literature [3]. Moreover, a combination of mucinous adenocarcinoma, goblet cell carcinoid, carcinoid tumor, and mature teratoma in an extragenital organ has not been reported. Herein, we present a rare case of combined mucinous adenocarcinoma and goblet cell and typical carcinoid tumor arising in mature cystic teratoma of the mesentery in a 48-year-old woman.

One of the major challenges in prostate cancer research is to identify prognostic/predictive factors to distinguish aggressive disease from indolent one. To select prognostic/predictive markers of postoperative biochemical recurrence (BCR) that could be easily performed in daily pathology practice, the expression of 6 immunohistochemical markers including zinc-α-2-glycoprotein (AZGP-1), hCAP-D3, mucin 1, vimentin, E-cadherin, and ERG was assessed in a tissue microarray of 400 radical prostatectomy specimens. The expression levels were correlated with clinicopathologic factors and BCR. During the median follow-up period of 55 months, BCR occurred in 70 cases (17.5%). Low expression of AZGP-1 was noted in 76 cases (19.0%), whereas high expression of hCAP-D3, mucin 1, vimentin, and ERG was observed in 205 (51.3%), 81 (20.3%), 33 (8.3%), and 58 (14.5%) cases, respectively. Aberrant E-cadherin expression was noted in 29 cases (7.3%). By univariate analysis, BCR was associated with low expression of AZGP-1, high expression of hCAP-D3, and aberrant expression of E-cadherin. By multivariate analysis, only AZGP-1 remained an independent immunohistochemical factor, in addition to age, preoperative serum prostate-specific antigen level, Gleason score, tumor stage, and resection margin status. These results show that AZGP-1, hCAP-D3, and E-cadherin are potentially useful immunohistochemical markers to predict BCR, and that AZGP-1 can be used as an independent prognostic marker of aggressive prostate cancer.

Intrahepatic cholangiocarcinomas occur mostly in the normal liver but they also arise in chronic advanced liver diseases. However, genetic differences between two groups have yet to be examined. High throughput mass spectrometry-based platform was used to interrogate mutations in intrahepatic cholangiocarcinomas and to compare the mutation profiles between 43 intrahepatic cholangiocarcinomas with normal liver and 38 with chronic advanced liver diseases. Forty seven mutations in 11 genes were identified in 38 of 81 cases (46.9%). The most commonly mutated gene was KRAS (11/81, 13.6%), followed by MLH1 (7/81, 8.6%), NRAS (7/81, 8.6%), GNAS (6/81, 7.4%), and EGFR (6/81, 7.4%). BRAF, APC, PIK3CA, CDKN2A, PTEN, and TP53 mutations were found with less than 5%. Overall mutation rate of intrahepatic cholangiocarcinomas with chronic advanced liver disease (15/38, 39.5%, 95% confidence interval: 23.9-55.0) was lower than that of intrahepatic cholangiocarcinomas with normal liver (23/43, 53.5%, 95% confidence interval: 38.5-68.3). Intrahepatic cholangiocarcinomas with chronic advanced liver disease showed higher EGFR mutation rate (5/38, 13.2% vs 1/43, 2.3%) and lower mutation rates of KRAS (3/38, 7.9% vs 8/43, 18.6%), MLH1 (2/38, 5.3% vs 5/43, 11.6%), and GNAS (1/38, 2.6% vs 5/43, 11.6%), compared with those in intrahepatic cholangiocarcinomas with normal liver. Mutations in PIK3CA, PTEN, CDKN2A, and TP53 were harbored only in intrahepatic cholangiocarcinomas with normal liver. KRAS (P=0.0075) or GNAS mutations (P=0.0256) were associated with poor overall survival in all patients with intrahepatic cholangiocarcinoma. Differential mutation patterns of intrahepatic cholangiocarcinomas with chronic advanced liver disease suggest different cholangiocarcinogenesis depending upon the predisposing factors, and support that different strategy for targeted therapy should be applied in intrahepatic cholangiocarcinoma subtypes.

PURPOSE: Cervical cytology and human papillomavirus (HPV) DNA co-testing is recommended as a screening method for detecting cervical lesions. However, for women who are HPV-positive but cytology-negative, the appropriate management and significance of HPV-58 infection remain unknown. METHODS: This study of prevalent HPV detected at baseline with a median follow-up of 3.2 years evaluated the risk factors associated with cervical abnormalities and assessed the significance of HPV-58 infection. A total of 265 women were enrolled. All high-grade squamous intraepithelial lesions (HSIL) that were detected by cytology were confirmed by histology. Histological diagnoses of cervical intraepithelial neoplasia 2/3 were classified as HSIL. Women were classified into four groups according to the HPV genotype that was detected at their first visit: HPV-58 (n = 27), HPV-16 (n = 52; 3 women had HPV-58 co-infection), ten other high risk (HR) types (n = 79), or low/undetermined risk types (n = 107). RESULTS: Of 265 women, 20 (7.5%) had HSIL on their follow-up examinations. There were significant differences in the cumulative incidence of HSIL between the four groups (p

Difference in prognosis between grade 3 endometrioid carcinoma (G3EC) of the endometrium and uterine serous carcinoma (USC) is controversial. In this study, we further evaluated the difference in prognosis, if any, between G3EC (n = 61) and USC (n = 47) on a total of 565 patients with endometrial cancer. In addition, meta-analysis was performed using data from seven previous publications (n = 8,637) and from the Asan Medical Center (n = 108). Regarding the cases from our institution, USC tended to occur in older patients (≥65 years) than G3EC (P = 0.011). Deep myometrial invasion (more than or equal to half) was more frequently identified in G3EC (36/61, 59.0 %) than in USC (17/47, 36.2 %) (P = 0.021). Between patients with early stage G3EC and USC (stages I and II), there were no significant differences in any clinicopathological parameter, but there was a significant difference in overall survival (P = 0.017) that was not found in advanced stage (P = 0.588). USC was an independent prognostic factor for poor overall survival (hazard ratio, 6.125; P = 0.030) in early stage patients. In the meta-analysis on 5-year survival in patients with early stage cancers, which also included our study results, a higher relative risk (1.92, 95 % CI 1.62–2.27) was demonstrated in USC than in G3EC (P

Trastuzumab in association with systemic cytotoxic chemotherapy is the standard of care for patients with advanced HER2-positive gastric carcinoma (GC). However, HER2 as a prognostic factor in GC remains controversial. HER2 overexpression and amplification was evaluated by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 2,798 GCs obtained from 2,727 gastrectomy and 71 open/laparoscopic biopsy specimens from patients with peritoneal seeding. Regional heterogeneity was defined as the proportion of tumor cells showing membranous staining in 10–70 % of tumor cells. Genetic heterogeneity was determined by the existence of HER2/CEP17 ratio higher than 2.0 in >5 to

Objective Immune competence is an important prognostic factor in cancer patients. Surgical management of cancer can cause a variety of immunological disturbances, the clinical consequences of which are still unclear. Materials and methods Patients with clinically staged cervical carcinoma (IB to IIA) who were treated at Samsung Medical Center, Seoul, Korea from 1994 to 2007 were retrospectively enrolled. We compared peri-operative peripheral lymphocyte counts, tumor-infiltrating lymphocyte scores, and survival in patients with early cervical cancer treated by abdominal type III radical hysterectomy. Results The sample included 756 patients. The median follow-up was 58months with a range of 3–181months. There was a positive correlation between pre-operative peripheral lymphocyte counts and tumor infiltrating lymphocyte score. Pre-operative peripheral lymphocyte counts decreased significantly after surgery. In multivariate analyses for recurrence, higher pre-operative peripheral lymphocyte counts and recovery of lymphocyte counts (more than 100/μL from the pre-operative level) on post-operative day 3 were independent positive prognostic factors and LN metastasis was negatively associated with post-operative recovery of peripheral lymphocyte counts. Conclusion Peripheral lymphocyte counts after cervical cancer surgery are important prognostic factors, and management aimed at minimizing immune disturbances after surgery should be assessed, especially in patients with LN metastasis.

The standard treatment for high grade ovarian serous cancer (HG-OSC) is aggressive cytoreductive surgery followed by platinum based chemotherapy. However, approximately 30% of patients exhibit platinum resistance, and those patients show aggressive clinical courses. Currently, it is difficult to predict which HG-OSC patients will respond to platinum-based chemotherapy.We analyzed whole exome sequences for 174 HG-SOC patients using data obtained from The Cancer Genome Atlas (TCGA) data portal regarding platinum response. Patients were categorized as having either hypermutation or hypomutation according to the number of mutations in their sample.HG-SOC showed multiple somatic mutations in individual patients with an average mutated gene number of 61.9. The mean mutation number per patient significantly differed between the platinum sensitive and resistant groups (P0.001). Patients who were platinum sensitive were more likely to have somatic hypermutation in their cancer cells and multivariate logistic regression analysis revealed that somatic hypermutation was an independent factor for risk estimation of platinum sensitivity (odds ratio [OR]=3.616; P=0.002). In multivariate Cox hazard analysis, we identified that somatic hypermutation, as well as platinum response and surgical outcome, were independent prognostic factors in HG-OSC (overall survival, P=0.012; progression free survival, P=0.036).Somatic hypermutation was significantly associated with platinum sensitivity and was an independent prognostic factor in HG-OSC patients treated with platinum based chemotherapy.

Objective: Patient age is one important factor used to evaluate the risk in women with ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion). This finding may be associated with atrophic changes reflecting a hypoestrogenic status and suggests that body mass index (BMI) can affect the outcome of ASC-H smears in postmenopausal women. Study Design: We investigated the outcome of 154 postmenopausal women with an ASC-H smear and assessed relationships with BMI categories and serum estradiol levels. Results: In patients with higher BMI, an underlying squamous intraepithelial lesion (SIL) was more frequent than in patients with lower BMI, and a higher BMI was also associated with increased serum estradiol levels. When samples were classified by preparation method, these findings were more pronounced in liquid-based smears than in conventional smears. Principal component analysis using three factors (BMI, age and human papilloma virus status) revealed two distinct groups: those with a negative cervical smear and those with a smear result indicating SIL+. Conclusion: Hormonal alterations can affect the outcome of ASC-H smears, and BMI is one factor that should be considered when evaluating the risk associated with ASC-H smears in postmenopausal women.

Objective 67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC). Methods 67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells. Results 67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage ( P =0.001). Patients with 67LR expression had shorter progression-free survival among all the patients ( P =0.010) and in particular among patients with advanced stages ( P =0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis. Conclusion These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.

A 46-year-old woman presented with whole abdominal discomfort, and imaging revealed a 3-cm-sized ill-defined ovarian mass with extensive peritoneal carcinomatosis. Histologic examination showed malignant fibrous histiocytoma of ovary with predominant myxoid stroma. Microscopic examination showed a highly cellular neoplasm composed of fibroblast-like cells with a predominant myxoid stroma and high pleomorphism and mitotic activity. Immunohistochemically, the tumor was negative for smooth muscle actin, desmin, S-100, pancytokeratin, c-kit, epithelial membrane antigen, and calretinin. Malignant fibrous histiocytoma of ovary is extremely rare, with only six previously reported cases. To the best of our knowledge, the myxoid type of malignant fibrous histiocytoma of ovary has not been previously reported in the English literature except for a case arising in a dermoid cyst of ovary. We present the case and briefly discuss the differential diagnosis.

Twist1 is known to be involved in epithelial-mesenchymal transition (EMT) and tumor progression. However, its specific role is different depending on the type of cancer. The functional role and clinical significance of Twist1 in esophageal squamous cell carcinoma (ESCC) have been rarely studied.We examined Twist1 expression in a total of 199 samples using immunohistochemistry and real-time reverse-transcription polymerase chain reaction (RT-PCR). We also studied the association of Twist1 with EMT of ESCC using tissue samples and in vitro models. In addition, we examined the changes in the whole-genome expression profiles of two ESCC cell lines after inducing upregulation of Twist1.Twist1 expression was increased in ESCC compared with that of normal esophagus (P 0.01). We found that expression of Twist1 was strongly associated with poor prognosis on both univariate analysis [relative risk (RR) = 3.019, P = 0.000] and multivariate analysis (RR = 3.131, P = 0.000). In addition, we found that Twist1 expression was strongly correlated with EMT in ESCC tissues. Upregulation of Twist1 induced other EMT inducers in all three esophageal cancer cell lines investigated (TE1, TE8, and TE10). Twist1 also enhanced the migratory and invasive abilities of all three cell lines. Finally, microarray analysis of gene expression in the three ESCC cell lines revealed that Twist1 upregulation affected the expression of mainly cytoskeleton and extracellular matrix-related genes, which are directly related to cell morphology and movement.Our study indicates that Twist1 is associated with EMT of esophageal squamous cell carcinoma and may be used as a diagnostic and prognostic biomarker in ESCC.