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1.  Prognostic Significance of BCL9 Expression in Hepatocellular Carcinoma 
Korean Journal of Pathology  2013;47(2):130-136.
Background
BCL9 enhances 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. The goal of this study was to elucidate the prognostic significance of BCL9 protein expression in hepatocellular carcinoma (HCC) patients.
Methods
We evaluated BCL9 protein expression by immunohistochemistry in tumor tissue from 288 primary HCC patients who underwent curative hepatectomy. The impact of BCL9 expression on the survival of the patients was analyzed. The median follow-up period was 97.1 months.
Results
Nuclear BCL9 protein expression was observed in 74 (25.7%) of the 288 HCCs. BCL9 expression was significantly associated with younger age (p=0.038), higher Edmondson grade (p=0.001), microvascular invasion (p=0.013), and intrahepatic metastasis (p=0.017). Based on univariate analyses, BCL9 expression showed an unfavorable influence on both disease-free survival (DFS, p=0.012) and disease-specific survival (DSS, p=0.032). Multivariate analyses revealed that higher Barcelona Clinic Liver Cancer stage was an independent predictor of both shorter DFS (p<0.001) and shorter DSS (p<0.001). BCL9 expression tended to be an independent predictor of shorter DFS (p=0.078).
Conclusions
BCL9 protein expression might be a marker of shorter DFS in HCC patients after curative hepatectomy.
doi:10.4132/KoreanJPathol.2013.47.2.130
PMCID: PMC3647125  PMID: 23667372
BCL9; Carcinoma, hepatocellular; Recurrence; Survival
2.  Metadherin Is a Prognostic Predictor of Hepatocellular Carcinoma after Curative Hepatectomy 
Gut and Liver  2013;7(2):206-212.
Background/Aims
The prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rate of 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<0.001), higher Edmondson grade (p<0.001), microvascular invasion (p<0.001), higher American Joint Committee on Cancer T stage (p=0.001), and higher α-fetoprotein level (p=0.003). Multivariate analyses revealed that high MTDH expression (p=0.014), higher Barcelona-Clinic Liver Cancer (BCLC) stage (p<0.001), and Edmondson grade III (p=0.042) were independent predictors of shorter disease-free survival (DFS). Higher BCLC stage (p<0.001) and Edmondson grade III (p=0.047) were also independent predictors of shorter disease-specific survival.
Conclusions
High MTDH expression may be a prognostic predictor of shorter DFS in HCC patients after curative hepatectomy.
doi:10.5009/gnl.2013.7.2.206
PMCID: PMC3607775  PMID: 23560157
Metadherin; Hepatocellular carcinoma; Survival
3.  CHD1L Is a Marker for Poor Prognosis of Hepatocellular Carcinoma after Surgical Resection 
Korean Journal of Pathology  2013;47(1):9-15.
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.
doi:10.4132/KoreanJPathol.2013.47.1.9
PMCID: PMC3589617  PMID: 23482400
CHD1L; Carcinoma, hepatocellular; Survival
4.  Diagnosis of gastric epithelial neoplasia: Dilemma for Korean pathologists 
The histopathological diagnosis of gastric mucosal biopsy and endoscopic mucosal resection/endoscopic submucosal dissection specimens is important, but the diagnostic criteria, terminology, and grading system are not the same in the East and West. A structurally invasive focus is necessary to diagnose carcinoma for most Western pathologists, but Japanese pathologists make a diagnosis of cancer based on severe dysplastic cytologic atypia irrespective of the presence of invasion. Although the Vienna classification was introduced to reduce diagnostic discrepancies, it has been difficult to adopt due to different concepts for gastric epithelial neoplastic lesions. Korean pathologists experience much difficulty making a diagnosis because we are influenced by Japanese pathologists as well as Western medicine. Japan is geographically close to Korea, and academic exchanges are active. Additionally, Korean doctors are familiar with Western style medical terminology. As a result, the terminology, definitions, and diagnostic criteria for gastric intraepithelial neoplasia are very heterogeneous in Korea. To solve this problem, the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists has made an effort and has suggested guidelines for differential diagnosis: (1) a diagnosis of carcinoma is based on invasion; (2) the most important characteristic of low grade dysplasia is the architectural pattern such as regular distribution of crypts without severe branching, budding, or marked glandular crowding; (3) if nuclear pseudostratification occupies more than the basal half of the cryptal cells in three or more adjacent crypts, the lesion is considered high grade dysplasia; (4) if severe cytologic atypia is present, careful inspection for invasive foci is necessary, because the risk for invasion is very high; and (5) other structural or nuclear atypia should be evaluated to make a final decision such as cribriform pattern, papillae, ridges, vesicular nuclei, high nuclear/cytoplasmic ratio, loss of nuclear polarity, thick and irregular nuclear membrane, and nucleoli.
doi:10.3748/wjg.v17.i21.2602
PMCID: PMC3110921  PMID: 21677827
Intraepithelial neoplasia; Stomach; Dysplasia; Adenoma; Carcinoma; Japanese; Western; Consensus; Vienna
5.  Promoter Methylation of E-cadherin in Hepatocellular Carcinomas and Dysplastic Nodules 
Journal of Korean Medical Science  2005;20(2):242-247.
In order to clarify the significance of E-cadherin methylation in multistep hepatocarcinogenesis, we examined the methylation status of the E-cadherin promoter region, using methylation-specific polymerase chain reaction in 64 hepatocellular carcinomas (HCCs) and 13 dysplastic nodules (DNs), and correlated these results with E-cadherin protein expression and clinicopathologic factors of HCCs. Promoter methylation was detected in 1 of 13 (7.7%) DNs, in 5 of 13 (38.5%) Edmondson and Steiner grade I HCCs, and in 27 of 51 (52.9%) grade II or III HCCs, and a significant correlation was observed between the methylation status and the stepwise progression of hepatocarcinogenesis (p=0.004). Reduced E-cadherin immunoreactivity was found in 18 of 64 (28%) HCCs, but in none of DNs. E-cadherin methylation status in HCCs was significantly correlated with microvascular invasion (p=0.02) and tumor recurrence (p=0.04), but not with reduced E-cadherin immunoreactivity. The Kaplan-Meier method showed that methylation status did not have a significant influence on the recurrence-free survival of HCC patients (p=0.15). Our results indicate that methylation of the E-cadherin promoter region is a frequent event in HCC, which may play an important role in the stepwise progression of hepatocarcinogenesis. And the promoter methylation of E-cadherin in HCC was found to be significantly correlated with microvascular invasion and recurrence.
doi:10.3346/jkms.2005.20.2.242
PMCID: PMC2808600  PMID: 15831995
Carcinoma, Hepatocellular; Dysplastic Nodule; Cadherins; DNA Methylation
6.  Poorly differentiated component in gastric pinch biopsies predicts submucosal invasion 
Diagnostic Pathology  2014;9:34.
Background
Endoscopic resection has become standard therapy for selected patients with early gastric carcinoma (EGC). However, the preoperative diagnostic accuracy for excluding submucosal (SM) invasion is not precise. Moreover, histologic features predicting SM invasion in gastric carcinomas (SMiGC) have not been studied extensively.
Methods
Pre-treatment gastric biopsies from 60 patients with SM invasion who underwent endoscopic resection were reviewed and compared to 58 biopsies of lesions confirmed to be intramucosal carcinomas (IMC). For validation of the results, an independent cohort consisting of 616 gastric biopsies confirmed as EGC were analyzed. For statistical analyses, χ-square test, Fisher’s exact test and multiple logistic progression tests were used.
Results
In the biopsy specimens of patients with SMiGCs, differentiated histology, poorly differentiated component, wisps of muscularis mucosa, tumor cribriforming, papillary architecture, desmoplasia and intraglandular eosinophilic necrotic debris (IEND) were observed in 96.7%, 36.7%, 16.7%, 16.7%, 23.3%, 40%, and 46.7% of cases, respectively, while the same features were observed in 100%, 5.2%, 0%, 1.7%, 5.2%, 19%, and 22.4% of biopsies with IMC. In multivariate analyses, poorly differentiated component [odds ratio (OR), 9.59, p = 0.002], IEND [OR, 6.23, p = 0.012], tumor cribriforming [OR, 4.66, p = 0.03] and papillary architecture [OR, 5.52, p = 0.018] were significantly associated with the detection of SM invasion. In the validation cohort, poorly differentiated component (p = 0.003) and papillary architecture (p = 0.008) remained significant.
Conclusion
Poorly differentiated component and papillary architecture are significant histopathologic predictors of SM invasion in pretreatment gastric biopsies of lesions considered for endoscopic therapy. Additional prospective studies are warranted to confirm our findings.
Virtual slide
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1588557731103084
doi:10.1186/1746-1596-9-34
PMCID: PMC3938134  PMID: 24555807
Gastric cancer; Biopsy; Histologic; Submucosa; Invasion; Endoscopic resection
7.  Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas 
Background
To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases.
Methods
We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval).
Results
In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65–221 structural variations (SVs) in primary tumors and 60–232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis.
Conclusions
We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments.
doi:10.1186/1755-8794-7-2
PMCID: PMC3896667  PMID: 24405831
Cancer; Hepatocellular carcinomas (HCC); Lung metastasis; Somatic; Next-generation sequencing (NGS)
8.  Exome Sequencing Identifies Early Gastric Carcinoma as an Early Stage of Advanced Gastric Cancer 
PLoS ONE  2013;8(12):e82770.
Gastric carcinoma is one of the major causes of cancer-related mortality worldwide. Early detection and treatment leads to an excellent prognosis in patients with early gastric cancer (EGC), whereas the prognosis of patients with advanced gastric cancer (AGC) remains poor. It is unclear whether EGCs and AGCs are distinct entities or whether EGCs are the beginning stages of AGCs. We performed whole exome sequencing of four samples from patients with EGC and compared the results with those from AGCs. In both EGCs and AGCs, a total of 268 genes were commonly mutated and independent mutations were additionally found in EGCs (516 genes) and AGCs (3104 genes). A higher frequency of C>G transitions was observed in intestinal-type compared to diffuse-type carcinomas (P = 0.010). The DYRK3, GPR116, MCM10, PCDH17, PCDHB1, RDH5 and UNC5C genes are recurrently mutated in EGCs and may be involved in early carcinogenesis.
doi:10.1371/journal.pone.0082770
PMCID: PMC3871845  PMID: 24376576
9.  GSTT1 Copy Number Gain and ZNF Overexpression Are Predictors of Poor Response to Imatinib in Gastrointestinal Stromal Tumors 
PLoS ONE  2013;8(10):e77219.
Oncogenic mutations in gastrointestinal stromal tumors (GISTs) predict prognosis and therapeutic responses to imatinib. In wild-type GISTs, the tumor-initiating events are still unknown, and wild-type GISTs are resistant to imatinib therapy. We performed an association study between copy number alterations (CNAs) identified from array CGH and gene expression analyses results for four wild-type GISTs and an imatinib-resistant PDGFRA D842V mutant GIST, and compared the results to those obtained from 27 GISTs with KIT mutations. All wild-type GISTs had multiple CNAs, and CNAs in 1p and 22q that harbor the SDHB and GSTT1 genes, respectively, correlated well with expression levels of these genes. mRNA expression levels of all SDH gene subunits were significantly lower (P≤0.041), whereas mRNA expression levels of VEGF (P=0.025), IGF1R (P=0.026), and ZNFs (P<0.05) were significantly higher in GISTs with wild-type/PDGFRA D842V mutations than GISTs with KIT mutations. qRT-PCR validation of the GSTT1 results in this cohort and 11 additional malignant GISTs showed a significant increase in the frequency of GSTT1 CN gain and increased mRNA expression of GSTT1 in wild-type/PDGFRA D842V GISTs than KIT-mutant GISTs (P=0.033). Surprisingly, all four malignant GISTs with KIT exon 11 deletion mutations with primary resistance to imatinib had an increased GSTT1 CN and mRNA expression level of GSTT1. Increased mRNA expression of GSTT1 and ZNF could be predictors of a poor response to imatinib. Our integrative approach reveals that for patients with wild-type (or imatinib-resistant) GISTs, attempts to target VEGFRs and IGF1R may be reasonable options.
doi:10.1371/journal.pone.0077219
PMCID: PMC3790698  PMID: 24124608
10.  Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma 
Oncology Letters  2012;4(2):213-220.
Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors characterized by a multistep process of tumor development. Nodular lesions that differ from the surrounding liver parenchyma and are characterized by cytological or structural atypia are termed dysplastic nodules (DNs). DNs are well-known precancerous HCC lesions. Expression of keratin (K) 19 and K7, molecular markers of hepatic progenitor cells and cholangiocytes, has been reported in certain HCCs. However, it remains unclear whether K19-positive HCC cells are derived from true hepatic progenitor cells or mature cells that have undergone a dedifferentiation or a transdifferentiation process. In total, 107 tissue sections (13 low-grade DNs, 15 high-grade DNs, 27 small HCCs and 52 large HCCs) from resected liver samples and 132 HCC tissue microarray (TMA) cores were subjected to immunohistochemical analysis for K19 and K7. Clinicopathological data of the HCC patients were evaluated. K19 expression was found in 0% of DNs, 19% of small HCCs (≤2 cm), 8% of large HCCs (>2 cm) and 8% of TMA samples. K7 expression was found in 14% of DNs, 41% of small HCCs, 15% of large HCCs and 6% of TMA samples. Among the five K19-positive small HCCs, four were distinctly nodular and one tumor was an infiltrative type. No vaguely nodular HCC was positive for K19. K19 expression was significantly associated with histological grade (P=0.023), serum α-fetoprotein level (P=0.001) and K7 expression (P=0.001) in HCC. K19 expression was an independent prognostic factor for overall survival in non-viral HCC patients (P=0.003). K19 expression is extremely rare in DNs and occurs in progressed small HCCs. Our results suggest that K19 expression may be an acquired feature of carcinoma cells during HCC progression in certain HCCs.
doi:10.3892/ol.2012.731
PMCID: PMC3402733  PMID: 22844356
carcinoma; hepatocellular; keratin; dysplastic nodule
11.  PIK3CA Mutations in Hepatocellular Carcinoma in Korea 
Yonsei Medical Journal  2013;54(4):883-887.
Purpose
Phosphatidylinositol 3-kinases/AKT pathway plays a pivotal role in hepatocellular carcinoma (HCC). Mutant PIK3CA, encoding the p110a catalytic subunit, stimulates the AKT pathway and promotes cell growth in various cancers. PIK3CA mutation rate has been usually reported as low frequency (<5%) in HCC except one report from Korea with 35.6%. Therefore, we investigated the frequency of PIK3CA mutations in Korean HCC patients.
Materials and Methods
We sequenced exons1, 3, 4, 6, 7, 8, 9, 19 and 20 of PIK3CA in 268 HCC tumor tissue samples by Sanger method and pyrosequencing assay.
Results
In this study, the mutations were not detected in exons3, 6, 8, and 19, and detected 1 at unknown SNP in exon1 and exon4, 2 at unknown SNP in exon7, 2 at unknown SNP in exon20. However, 1 at unknown SNP, 1 at G1635T and surprisingly all samples at A1634Cin exon9 were detected by Sanger method. Additional experiments with normal tissue, cloning experiments and a pyrosequencing assay revealed that the double peak at A1634C of exon9 is a pseudogene, not true mutation. The mutations found in this study were all different and small numbers, therefore, we cannot conclude specific relationship between clinical characteristics of HCC and mutation of PIK3CA.
Conclusion
Our study suggests that the rate of PIK3CA mutation in the Korea population is in fact similar to the rates seen elsewhere in the world.
doi:10.3349/ymj.2013.54.4.883
PMCID: PMC3663228  PMID: 23709421
PIK3CA; mutation; hepatocellular carcinoma
12.  Hepatoid adenocarcinoma of the stomach: an unusual case of elevated alpha-fetoprotein with prior treatment for hepatocellular carcinoma 
Clinical and molecular hepatology  2013;19(2):173-178.
Hepatoid adenocarcinoma (HAC) is a rare type of extrahepatic carcinoma whose morphology is similar to that of hepatocellular carcinoma (HCC). Metachronous HCC and HAC in the same patient is extremely rare. The case of a 68-year-old man with chronic hepatitis B infection who had both HCC and HAC of the stomach is reported herein. Nine years previously this patient had been diagnosed with HCC and received a right lobectomy. HCC that recurred at the caudate lobe at 6 months after the operation was successfully treated with transarterial chemoembolization. The patient was followed up regularly thereafter without evidence of tumor recurrence for 9 years. In July 2010 his serum alpha-fetoprotein (AFP) level elevated from 6.5 ng/mL to 625.4 ng/mL, and he developed a probable single metastatic lymph node around the hepatic artery without intrahepatic lesions. Subsequent evaluation with upper endoscopy revealed a 4-cm ulcerative lesion on the antrum of the stomach. Subtotal gastrectomy was performed with lymph-node dissection. Histologic examination revealed a special type of extrahepatic AFP-producing adenocarcinoma-HAC with lymph-node metastasis-which indicates that HAC can be a cause of elevated AFP even in patients with HCC. HAC should be considered if a patient with stable HCC exhibits unusual elevation of AFP.
doi:10.3350/cmh.2013.19.2.173
PMCID: PMC3701850  PMID: 23837142
Hepatoid adenocarcinoma; Hepatocellular carcinoma; Stomach; Metachronous
13.  Silent Colonic Malakoplakia in a Living-Donor Kidney Transplant Recipient Diagnosed during Annual Medical Examination 
Korean Journal of Pathology  2013;47(2):163-166.
Malakoplakia is a characteristic inflammatory condition, which is usually seen in the urogenital tract, and less frequently in the gastrointestinal tract. We present a case of colonic malakoplakia in an immunocompromised patient. A 55-year-old female visited the outpatient clinic for routine cancer surveillance. Her past medical history was significant for kidney transplantation 11 years ago, and she had been taking immunosuppressants. A colonoscopy revealed several depressed flat lesions and elevated polyps, which were 0.3 to 0.4 cm in size and accompanied by whitish exudates. A biopsy revealed an infiltration of histiocytes with ample granular eosinophilic cytoplasm, with some lymphocytes and plasma cells. Many histiocytes had the characteristic morphology, described as Michaelis-Gutmann bodies: one or several round basophilic structures of approximately 1 to 10 µm in size with some being laminated, some appearing homogeneous, and others having a dense central core with a targetoid appearance. These Michaelis-Gutmann bodies were positively stained on von Kossa stain, and were diagnostic for malakoplakia.
doi:10.4132/KoreanJPathol.2013.47.2.163
PMCID: PMC3647129  PMID: 23667376
Malakoplakia; Colon; Kidney transplantation
14.  The effect of alkaline phosphatase and intrahepatic metastases in large hepatocellular carcinoma 
Background
Hepatectomy is the standard treatment for HCC. However, large HCC poses a difficult challenge because of the technical complexity of surgical resection and the fear of postoperative hepatic decompensation. We analyzed the outcome and prognostic factors in patients with large hepatocellular carcinoma (HCC ≥10 cm) after surgery.
Methods
We retrospectively investigated the medical records of 91 patients who had undergone hepatectomy between January 2006 and June 2010. A survival analysis was performed utilizing the Kaplan-Meier method and prognostic factors were evaluated using Cox regression analysis.
Results
Of the 91 patients evaluated, most tumors were associated with hepatitis B virus (HBV). The median tumor size was 12.3 cm (range, 10 to 21 cm), with microvascular invasion present in most patients. The postoperative mortality rate was 2.2%. The median disease-free survival and overall survival were six months and 41 months. The one-year, two-year, and three-year disease-free survival rates were 33.5%, 29.3%, and 18.8%, respectively. The one-year, two-year, and three-year overall survival rates were 73.9%, 63.7%, and 54.8%, respectively. Of the 89 surviving patients, 69 patients (77.5%) developed HCC recurrence during the mean follow-up period of 23.4 ± 15.9 months. On multivariate analysis, the statistically significant factors that predicted HCC recurrence were ALP ≥ 80 IU/mL (P = 0.009) and intrahepatic metastases (P = 0.013).
Conclusions
Our study suggests that preoperative ALP levels (≥ 80 IU/L) and intrahepatic metastases could be utilized to monitor and predict recurrence in HCC patients.
doi:10.1186/1477-7819-11-40
PMCID: PMC3598399  PMID: 23432910
Hepatocellular carcinoma; Liver resection; Metastasis; Survival
15.  Low SP1 Expression Differentially Affects Intestinal-Type Compared with Diffuse-Type Gastric Adenocarcinoma 
PLoS ONE  2013;8(2):e55522.
Specificity protein 1 (SP1) is an essential transcription factor that regulates multiple cancer-related genes. Because aberrant expression of SP1 is related to cancer development and progression, we focused on SP1 expression in gastric carcinoma and its correlation with disease outcomes. Although patient survival decreased as SP1 expression increased (P<0.05) in diffuse-type gastric cancer, the lack of SP1 expression in intestinal-type gastric cancer was significantly correlated with poor survival (P<0.05). The knockdown of SP1 in a high SP1-expressing intestinal-type gastric cell line, MKN28, increased migration and invasion but decreased proliferation. Microarray data in SP1 siRNA-transfected MKN28 revealed that the genes inhibiting migration were downregulated, whereas the genes negatively facilitating proliferation were increased. However, both migration and invasion were decreased by forced SP1 expression in a low SP1-expressing intestinal-type gastric cell line, AGS. Unlike the intestinal-type, in a high SP1-expressing diffuse-type gastric cell line, SNU484, migration and invasion were decreased by SP1 siRNA. In contrast to previous studies that did not identify differences between the 2 histological types, our results reveal that low expression of SP1 is involved in cancer progression and metastasis and differentially affects intestinal-type compared with diffuse-type gastric adenocarcinoma.
doi:10.1371/journal.pone.0055522
PMCID: PMC3577840  PMID: 23437057
16.  Neuroendocrine tumor in gastric adenoma: a diagnostic pitfall mimicking invasive adenocarcinoma 
Diagnostic Pathology  2012;7:102.
Neuroendocrine tumor (NET) in adenoma of the gastrointestinal tract is a rare mixed glandular-endocrine neoplasm and has uncommonly been described mostly in the colon. Histologically, this tumor is composed of a predominant proportion of benign adenomatous component and a small portion of well-differentiated NE component. Only three cases of NET in gastric adenoma have been reported in the literature. We present 4 cases of NET in gastric adenoma mimicking invasive adenocarcinoma. The NETs were 0.62 mm to 4.1 mm in size and located at the basal lamina propria, muscularis mucosa and submucosa. Histologically, NETs consisted of nests, cords, tubules, and clusters of cells that predominantly interposed between the foveolar base without disturbing the overall polyp architecture. The lesions were completely removed by endoscopic submucosal dissection in three cases and in one case, subtotal gastrectomy was performed because endoscopic biopsy was invasive adenocarcinoma. The patients’ clinical course was uneventful without an evidence of recurrence or metastasis. The recognition of NET in gastric adenoma will help avoid potential diagnostic pitfalls masquerading as invasvie adenocarcinomas posed by their infiltrative pattern into submucosa.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1688552293761001
doi:10.1186/1746-1596-7-102
PMCID: PMC3487888  PMID: 22894753
Neuroendocrine tumor; Adenoma; Microcarcinoid; Diagnosis
17.  Gastric Adenocarcinoma of Fundic Gland Type: Report of Three Cases 
Korean Journal of Pathology  2012;46(3):287-291.
Recently, fundic gland type gastric adenocarcinoma (GA-FG) has been reported as a new entity. This report describes GA-FG among Koreans for the first time. From March 2008 to July 2010 we identified only three cases of GA-FG out of over 6,000 GAs resected by endoscopy or surgery. Cell differentiation by mucin proteins, pepsinogen-I, and H+/K+-ATPase was evaluated. All three cases were male patients and diagnosed as early stage GA. Histologically, GA-FGs were well-differentiated adenocarcinoma with pale gray-blue, basophilic columnar or cuboidal cells and mildly enlarged nuclei, resembling chief cells. All three cases were positive for pepsinogen-I and were classified as gastric mucin phenotype. Among three histologic subtypes of GA-FG, since tumors were mainly composed of chief cells, our three cases were classified as chief cell predominant type. In conclusion, GA-FG is very rare among Koreans and pepsinogen-I and MUC6 expression are typical immunohistochemical findings in GA-FG suggesting differentiation toward fundic glands.
doi:10.4132/KoreanJPathol.2012.46.3.287
PMCID: PMC3479759  PMID: 23110017
Stomach neoplasms; Fundic gland; Chief cells, gastric; Cell differentiation; Pepsinogen A
18.  Glomus Tumor of the Stomach: A Clinicopathologic Analysis of 10 Cases and Review of the Literature 
Gut and Liver  2012;6(1):52-57.
Background/Aims
Gastric glomus tumors are extremely rare, and presurgical confirmation is often impossible. The identification of clinical and radiologic characteristics of this tumor type is important for preoperative diagnosis and treatment planning.
Methods
In this study, we analyzed 10 cases of gastric glomus tumors resected at a single institute over 9 years.
Results
Eight of the patients were men and 2 were women, with a mean age of 49 years. Five patients presented with abdominal discomfort or pain, 1 presented with anemia, and the remaining 4 cases were found incidentally during endoscopic examinations. The most common location of the tumor was the antrum (n=7), followed by the low (n=2) and high body (n=1). Although the endoscopic ultrasonography findings were variable, contrast-enhanced computed tomography generally showed a strong homogeneous enhancement. The resected tumors were well-demarcated solid masses with sizes ranging from 1.0 to 3.6 cm. Microscopically, the masses were composed of abundant vascular channels with clusters of uniform and round glomus cells. There was no evidence of recurrence after complete surgical resection.
Conclusions
Gastric glomus tumors are unusual, distinct lesions that should be considered in the differential diagnosis of a gastric submucosal mass. Unlike their deep soft tissue counterparts, most glomus tumors in the stomach are benign.
doi:10.5009/gnl.2012.6.1.52
PMCID: PMC3286739  PMID: 22375171
Glomus tumor; Stomach; Endoscopy; Pathology; Radiology
19.  The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy 
BMC Cancer  2011;11:344.
Background
Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear.
Methods
A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS) of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status.
Results
CIMP-high CRCs were identified in 34 cases (13.9%), and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP-high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100%) showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4%) (P = 0.022).
Conclusions
Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results.
doi:10.1186/1471-2407-11-344
PMCID: PMC3162585  PMID: 21827707
20.  Metastatic lymph node in gastric cancer; Is it a real distant metastasis? 
BMC Cancer  2010;10:25.
Background
Currently, the TNM staging system is a widely accepted method for assessing the prognosis of the disease and planning therapeutic strategies for cancer. Of the TNM system, the extent of lymph node involvement is the most important independent prognostic factor for gastric cancer. The aim of our study is to evaluate the survival and prognosis of gastric cancer patients with LN#12 or #13 involvement only and to assess the impact of anatomic regions of primary gastric tumor on survival in this particular subset of patients.
Methods
Among data of 1,008 stage IV gastric cancer patients who received curative R0 gastrectomy, a total of 79 patients with LN#12 (n = 68) and/or #13 (n = 11) were identified. All patients performed gastrectomy with D2 or D3 lymph node dissection.
Results
In 79 patients with LN#12/13 involvement, the estimated one-, three- and five-year survival rate was 77.2%, 41.8% and 26.6% respectively. When we compared the patients with LN#12/13 involvement to those without involvement, there was no significant difference in OS (21.0 months vs. 25.0 months, respectively; P = 0.140). However, OS was significantly longer in patients with LN#12/13 involvement only than in those with M1 lymph node involvement (14.3 months; P = 0.001). There was a significant difference in survival according to anatomic locations of the primary tumor (lower to mid-body vs. high body or whole stomach): 26.5 vs. 9.2 months (P = 0.009). In Cox proportional hazard analysis, only N stage (p = 0.002) had significance to predict poor survival.
Conclusion
In this study we found that curatively resected gastric cancer patients with pathologic involvement of LN #12 and/or LN #13 had favorable survival outcome, especially those with primary tumor location of mid-body to antrum. Prospective analysis of survival in gastric cancer patients with L N#12 or #13 metastasis is warranted especially with regards to primary tumor location.
doi:10.1186/1471-2407-10-25
PMCID: PMC2848187  PMID: 20113485
21.  Prediction of Complete Necrosis of Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Prior to Liver Transplantation 
Gut and Liver  2009;3(4):285-291.
Background/Aims
Compact lipiodol uptake without enhancement on multiphasic helical computed tomography (CT) has been suggested as a radiologic response criterion in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) and subsequent partial hepatectomy. However, its usefulness has not been fully investigated in the explanted liver.
Methods
Between 1998 and 2007, 81 patients with HCC underwent 1-9 sessions of TACE followed by liver transplantation (LT). Thirty-nine tumors in 29 patients showed a radiologic response on CT performed prior to LT. The radiologic response criteria and the duration of the response were evaluated to predict total necrosis in the explanted liver.
Results
Among the 39 tumors, 34 nodules (87.2%) exhibited total pathological necrosis. While 13 out of 16 tumors (81.3%) with a radiologic response for 6 months or less were completely necrotic, 21 out of 23 tumors (91.3%) with a radiologic response of longer than 6 months showed total necrosis.
Conclusions
Our results suggested that the radiologic response criteria based on serial CT images might be useful for predicting total necrosis of TACE-pretreated HCC in LT.
doi:10.5009/gnl.2009.3.4.285
PMCID: PMC2852730  PMID: 20431762
Explanted liver; Pathology; Computed tomography; Radiologic response
22.  The Clinicopathological Features of Gastric Hyperplastic Polyps with Neoplastic Transformations: A Suggestion of Indication for Endoscopic Polypectomy 
Gut and Liver  2009;3(4):271-275.
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.
doi:10.5009/gnl.2009.3.4.271
PMCID: PMC2852734  PMID: 20431760
Hyperplastic polyp; Neoplastic transformation; Endoscopic polypectomy
23.  Carney Triad in an Adult with Aggressive Behavior: The First Case in Korea 
Yonsei Medical Journal  2009;50(5):709-712.
Carney triad is a rare syndrome of unknown etiology characterized by having at least two out of three following neoplasms: gastrointestinal stromal tumor, pulmonary chondroma and extra-adrenal paraganglioma. About 100 cases have been reported worldwide. We report a case of Carney triad in a 42-year-old woman presented with a gastrointestinal stromal tumor in the stomach and a malignant functioning paraganglioma in the retroperitoneum that was fatal five years after diagnosis. The gastrointestinal stromal tumor was diagnosed as intermediate-risk of aggressive behavior and diffusely positive for c-kit whereas the retroperitoneal paraganglioma was negative for c-kit. Genetic analyses showed no mutations of KIT, PDGFRA, SDHB, SDHC, and SDHD genes in both tumors. To our best knowledge, this is the first case of Carney triad in Korea.
doi:10.3349/ymj.2009.50.5.709
PMCID: PMC2768248  PMID: 19881977
Carney triad; gastrointestinal stromal tumor; paraganglioma; malignant
24.  Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q 
To elucidate the pathogenesis of hepatocellular carcinoma (HCC) and develop useful prognosis predictors, it is necessary to identify biologically relevant genomic alterations in HCC. In our study, we defined recurrently altered regions (RARs) common to many cases of HCCs, which may contain tumor-related genes, using whole-genome array-CGH and explored their associations with the clinicopathologic features. Gene set enrichment analysis was performed to investigate functional implication of RARs. On an average, 23.1% of the total probes were altered per case. Mean numbers of altered probes are significantly higher in high-grade, bigger and microvascular invasion (MVI) positive tumors. In total, 32 RARs (14 gains and 18 losses) were defined and 4 most frequent RARs are gains in 1q21.1-q32.1 (64.5%), 1q32.1-q44 (59.2%), 8q11.21-q24.3 (48.7%) and a loss in 17p13.3-p12 (51.3%). Through focusing on RARs, we identified genes and functional pathways likely to be involved in hepatocarcinogenesis. Among genes in the recurrently gained regions on 1q, expression of KIF14 and TPM3 was significantly increased, suggesting their oncogenic potential in HCC. Some RARs showed the significant associations with the clinical features. Especially, the recurrent loss in 9p24.2-p21.1 and gain in 8q11.21-q24.3 are associated with the high tumor grade and MVI, respectively. Functional analysis showed that cytokine receptor binding and defense response to virus pathways are significantly enriched in high grade-related RARs. Taken together, our results and the strategy of analysis will help to elucidate pathogenesis of HCC and to develop biomarkers for predicting behaviors of HCC.
doi:10.1002/ijc.23901
PMCID: PMC2698448  PMID: 18803288
hepatocellular carcinoma; recurrently altered regions; array comparative genomic hybridization; KIF14; TPM3
25.  SPIO-Enhanced MRI Findings of Well-Differentiated Hepatocellular Carcinomas: Correlation with MDCT Findings 
Korean Journal of Radiology  2009;10(2):112-120.
Objective
This study was designed to assess superparamagnetic iron oxide (SPIO)-enhanced MRI findings of well-differentiated hepatocellular carcinomas (HCCs) correlated with their multidetector-row CT (MDCT) findings.
Materials and Methods
Seventy-two patients with 84 pathologically proven well-differentiated HCCs underwent triple-phase MDCT and SPIO-enhanced MRI at a magnetic field strength of 1.5 Tesla (n = 49) and 3.0 Tesla (n = 23). Two radiologists in consensus retrospectively reviewed the CT and MR images for attenuation value and the signal intensity of each tumor. The proportion of hyperintense HCCs as depicted on SPIO-enhanced T2- or T2*-weighted images were compared in terms of tumor size (< 1 cm and > 1 cm), five CT attenuation patterns based on arterial and equilibrium phases and magnetic field strength, by the use of univariate and multivariate analyses.
Results
Seventy-eight (93%) and 71 (85%) HCCs were identified by CT and on SPIO-enhanced T2- and T2*-weighted images, respectively. For the CT attenuation pattern, one (14%) of seven isodense-isodense, four (67%) of six hypodense-hypodense, four (80%) of five isodense-hypodense, 14 (88%) of 16 hyperdense-isodense and 48 (96%) of 50 hyperdense-hypodense HCCs were hyperintense (Cochran-Armitage test for trend, p < 0.001). Based on the use of multivariate analysis, the CT attenuation pattern was the only factor that affected the proportion of hyperintense HCCs as depicted on SPIO-enhanced T2- or T2*-weighted images (p < 0.001). Tumor size or magnetic field strength was not a factor that affected the proportion of hyperintense HCCs based on the use of univariate and multivariate analysis (p > 0.05).
Conclusion
Most well-differentiated HCCs show hyperintensity on SPIO-enhanced MRI, although the lesions show various CT attenuation patterns. The CT attenuation pattern is the main factor that affects the proportion of hyperintense well-differentiated HCCs as depicted on SPIO-enhanced MRI.
doi:10.3348/kjr.2009.10.2.112
PMCID: PMC2651447  PMID: 19270856
Well-differentiated hepatocellular carcinoma; Superparamagnetic iron oxide-enhanced MRI, MDCT

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