Characteristics of Gastric Carcinomas With High ERCC1 Expression and the Prognostic Value of ERCC1 Expression.

BACKGROUND/AIM: We aimed to evaluate the characteristics of gastric carcinoma with high excision repair cross complementing 1 (ERCC1) expression and the prognostic value of ERCC1 expression. MATERIALS AND METHODS: ERCC1 expression was evaluated by immunohistochemistry in 309 surgically resected gastric carcinoma specimens using a tissue microarray. Cancer-related survival was analysed using competing risk analysis. RESULTS: Compared to ERCC1-low gastric carcinomas, ERCC1-high gastric carcinomas showed less local invasion (p=0.0013), lower N stage (p=0.0302), earlier pTNM stage (p=0.0003), and less frequent recurrence (p=0002). Patients with ERCC1-high gastric carcinoma showed lower cumulative incidence function estimate of cancer-related death [3.37; 95% confidence intervaI (CI)=0.89-8.75] than did those with ERCC1-low gastric carcinoma (17.12; 95% CI=12.24-22.69; p-value by Gray's test=0.0012). Adjusted proportional sub-distribution hazard ratio for cancer-related death in the patients with ERCC1-high tumour was 0.272 (95% CI=0.084-0.878; p=0.0295). CONCLUSION: High ERCC1 expression may be an independent positive prognostic marker for gastric carcinoma.

Myoferlin silencing inhibits VEGFR2-mediated proliferation of metastatic clear cell renal cell carcinoma.

Recently, ramucirumab, a drug that targets vascular endothelial growth factor receptor (VEGFR), was clinically approved; therefore, we evaluated VEGFR2 expression and its predictive roles in tumor progression in clear cell renal cell carcinoma (CCRCC). Since we do not have many options for treating aggressive renal cell carcinoma patients, the application of anti-VEGFR2 therapy might be useful. Myoferlin (MYOF) is a 230 kDa transmembrane multi-C2-domain protein that contributes to plasma membrane repair, fusion, and endocytosis and is overexpressed in several invasive cancer cell lines, including breast, pancreas, and malignant melanoma. It forms a complex with VEGFR2 to inhibit VEGFR2 degradation. In this study, a total of 152 patients who had undergone nephrectomy for CCRCC were enrolled. Based on tissue microarray (TMA) blocks, the positive intensity and high proportion of MYOF showed a statistically significant correlation with the negative intensity (p < 0.001) and low proportion (p < 0.001) of VEGFR2, respectively. In addition, Fuhrman's nuclear grade ≥3 showed a significant correlation with VEGFR2 expression. In multivariate analysis, CCRCC patients with positive MYOF and negative VEGFR2 expression demonstrated poor clinical outcomes. We confirmed that positive MYOF expression and negative VEGFR2 expression were positively correlated in this CCRCC population. Knocking down MYOF in Caki-1 cells resulted in the downregulation of VEGFR2 at both mRNA and protein levels. Wound healing assays revealed that the loss of MYOF in Caki-1 cells decreased cell confluence compared to that in control cells. We demonstrated that MYOF influences cellular proliferation of the metastatic CCRCC cell line by regulating VEGFR2 degradation. Combined therapies targeting the MYOF and VEGFR2 pathways might be effective against metastatic CCRCC to increase patient survival.

Size distribution of serum extracellular vesicles in mice with atherosclerosis.

BACKGROUND AND AIMS: Atherosclerosis is a prominent vascular lesion, and potentially causing ischemic alterations in the brain and heart. Recent studies have reported that physiological and pathological alterations in atherosclerosis and extracellular vesicles (EV) are related. This study aimed to investigate the association between the extent of atherosclerotic lesions and the number of serum EVs in a mouse model of atherosclerosis (wild-type). METHODS: Eighteen 3-week-old C57BL/6 N male mice(wild-type) were purchased. Twelve mice were fed a 45% high-fat diet (HFD) for six months. Six mice were provided standard laboratory chow for six months. The entire aorta, from the aortic sinus to the division of the iliac artery, was dissected out from each mouse. Furthermore, the degree of atherosclerosis was microscopically determined. Serum EVs were quantified by size via nanoparticle tracking analysis. RESULTS: The number of EVs in the high-atherosclerotic score group (1.43 × 109) was higher than that in the low- atherosclerotic score group (0.7 × 109) in the range of 211.5-222.5 nm (p = 0.033). CONCLUSIONS: Enumeration of EVs is a potential method of detecting atherosclerosis.

RAB27A is an independent prognostic factor in clear cell renal cell carcinoma.

AIM: To examine the expression of RAB27A and RAB27B in clear cell renal cell carcinoma (CCRCC). MATERIALS & METHODS: The intensity and proportion of tumor cells staining positive for RAB27A and RAB27B in a total of 304 cores were evaluated. RESULTS: The T stage showed a significant correlation with RAB27A intensity (p < 0.001). In multivariate analysis, CCRCC with negative intensity of RAB27A expression demonstrated poor disease-specific survival (hazard ratio: 6.821, 95% CI: 1.128-41.241; p-value = 0.036). CONCLUSION: RAB27A is an independent prognostic factor in CCRCC.

Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung.

BACKGROUND: S100A8 and S100A9 have been gaining recognition for modulating tumor growthand metastasis. This study aimed at evaluating the clinical significance of S100A8 and S100A9 innon-small cell lung cancer (NSCLC). METHODS: We analyzed the relationship between S100A8and S100A9 expressions, clinicopathological characteristics, and prognostic significance in tumorcells and peritumoral inflammatory cells. RESULTS: The positive staining of S100A8 in tumorcells was significantly increased in male (p < .001), smoker (p = .034), surgical method other thanlobectomy (p = .024), squamous cell carcinoma (SQCC) (p < .001) and higher TNM stage (p = .022)compared with female, non-smoker, lobectomy, adenocarcinoma (ADC), and lower stage. Theproportion of tumor cells stained for S100A8 was related to histologic type (p < .001) and patientsex (p = .027). The proportion of inflammatory cells stained for S100A8 was correlated with patientage (p = .022), whereas the proportion of inflammatory cells stained for S100A9 was correlatedwith patient sex (p < .001) and smoking history (p = .031). Moreover, positive staining in tumorcells, more than 50% of the tumor cells stained and less than 30% of the inflammatory cellsstained for S100A8 and S100A9 suggested a tendency towards increased survivability in SQCCbut towards decreased survivability in ADC. CONCLUSIONS: S100A8 and S100A9 expressions might be potential prognostic markers in patients with NSCLC.

Investigation of Clinical and Pathological Relationships between Adult- and Pediatric-type NASH in Korean Children.

BACKGROUND: Histologically, nonalcoholic steatohepatitis (NASH) is categorized into adult-type (type 1) and pediatric-type (type 2). The origination of the histological difference between the two types and how they differ clinically remain uncertain. We aimed to understand the incidence and clinical characteristics of the two types of NASH in Korean children, and to investigate the association between their pathological type and clinical characteristics, using anthropometric and laboratory data. METHODS: In 38 children with confirmed NASH, we investigated hepatic pathological findings, and correlating factors between pathological type and laboratory and anthropometric data (weight percentile, body mass index (BMI) z-score, and blood pressure percentile). Adult-type NASH was noted in 21 patients and pediatric-type in 17 patients. RESULTS: Age, sex, BMI, transaminase levels, and insulin resistance were not significantly different between the two groups. Triglyceride (TG) levels were higher in adult-type NASH (P = 0.033). Hematocrit and albumin levels were lower in adult-type NASH (P = 0.016 and 0.013, respectively). Hepatic fibrosis was more common in pediatric-type. The fibrosis scores in patients with adult-type were mostly 0 and 1, whereas the score was 3 in patients with pediatric-type (P = 0.024, 0.004, and < 0.010, respectively). Anthropometric data, liver function, and insulin resistance scores did not differ between the two pathological NASH types. TG, hematocrit, and albumin may be potential factors to predict pathological types. Fibrosis was observed more frequently in pediatric-type NASH. CONCLUSION: Monitoring children with pediatric-type NASH for progression to fibrosis or cirrhosis is recommended.

Loss of Wnt7a expression correlates with tumor progression and poor prognosis in colorectal carcinoma.

Wnt7a is a known tumor suppressor gene in non-small cell lung cancer that regulates normal cellular proliferation and differentiation. The purpose of this study was to investigate the clinicopathologic significance of Wnt7a expression in colorectal adenocarcinoma. Wnt7a expression was immunohistochemically examined in 46 normal colorectal tissues, 47 tubular adenomas, 393 adenocarcinomas, and 93 lymph node metastases. Wnt7a was expressed in the cytoplasm. Loss of Wnt7a expression was more frequent in adenocarcinoma and lymph node metastasis compared to that in normal and tubular adenoma (P < 0.001). Wnt7a expression was inversely correlated with tumor size (P = 0.026), gross type (P = 0.008), differentiation (P = 0.009), vascular invasion (P = 0.038), tumor deposit (P = 0.007), tumor invasion (T category) (P = 0.003), lymph node metastasis (N category) (P < 0.001), and AJCC stage (P < 0.001). There was a significant correlation between loss of Wnt7a expression and overall survival and disease-free survival (P < 0.001 and P = 0.001, respectively) on univariable analysis. On multivariable analysis, loss of Wnt7a expression was an independent prognostic factor for both overall and disease-free survival (P = 0.002 and P = 0.047, respectively). Loss of Wnt7a expression may contribute to the carcinogenesis and tumor progression of colorectal adenocarcinoma and may be a new prognostic marker of colorectal adenocarcinoma.

Intravascular large B-cell lymphoma associated with myelofibrosis: A case report.

Myelofibrosis (MF) is often accompanied by chronic myeloid leukemia, hairy cell leukemia, or certain primary myeloproliferative neoplasms, but is rarely associated with lymphoid neoplasms. We herein describe a case of intravascular large B-cell lymphoma (IVLBCL) with MF. IVLBCL is a rare, aggressive type of extranodal B-cell lymphoma, defined by proliferation of lymphomatous cells within small-to medium-sized vessels. A 60-year-old woman was admitted to the hospital with anemia, thrombocytopenia and fever. Bone marrow biopsy findings included trilineage hematopoiesis, increased numbers of immature cells, markedly abnormal and enlarged megakaryocytes, and diffuse fibrosis in multiple focal areas throughout the entire bone marrow space. When the patient was first hospitalized, hepatosplenomegaly was not present. Although initially considered during differential diagnosis, an aggressive lymphoma could not be diagnosed prior to colonoscopy, which was conducted 4 weeks after admission. A biopsy of the terminal ileum revealed IVLBCL with cells with atypical nuclei. Immunophenotyping of the atypical large cells yielded a positive result for CD79a and negative results for terminal deoxynucleotidyl transferase, myeloperoxidase, CD3, CD10, CD20, B-cell lymphoma (Bcl)-2, Bcl-6 and cytomegalovirus. The patient was diagnosed with IVLBCL complicated by MF. This case may serve as a reminder that IVLBCL may be the cause of secondary MF.

Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis.

PURPOSE: Insulin resistance (IR) has an important role in the development of non-alcoholic steatohepatitis (NASH). We aimed to analyze the association between liver histopathology and IR in pediatric patients with NASH. MATERIALS AND METHODS: In 24 children with non-alcoholic fatty liver disease (NAFLD), we investigated whether the hepatic pathologic characteristics have relations with following three biochemical indices; IR index including homeostasis model assessment of IR (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity indices-free fatty acid (ISI-FFA). RESULTS: Among 24 patients, 16 (66.6%) had a high NAFLD activity score (NAS), which is diagnostic of NASH. Higher serum triglyceride level was significantly correlated with a high NAS. Higher steatosis grades were significantly associated with low insulin sensitivity (p=0.023). In addition, severe lobular inflammation was associated with higher IR: HOMA-IR (p=0.014) and QUICKI (p=0.023). Severe fibrosis correlated with low insulin sensitivity and high IR indexes: ISI-FFA (p=0.049), HOMA-IR (p=0.028), and QUICKI (p=0.007). CONCLUSION: Patients with high IR had more severe lobular inflammation and hepatic fibrosis. Analyses of biochemical and endocrine parameters can be applied to determine the severity of the hepatic pathologic status in patients with NASH, especially in children who cannot undergo a liver biopsy.

Clinicopathologic Significance of Extranodal Tumor Extension in Colorectal Adenocarcinoma with Regional Lymph Node Metastasis.

Background. This study investigated the clinicopathologic significance of extranodal tumor extension in colorectal adenocarcinoma with lymph node metastasis. Method. Included were 419 patients who underwent curative resection for primary colorectal adenocarcinoma. Results. Extranodal tumor extension was observed more frequently in tumors with ulceroinfiltrative gross type (p = 0.026), higher histologic grade (p = 0.012), high grade tumor budding (p = 0.003), vascular invasion (p < 0.001), perineural invasion (p = 0.015), tumor deposit (p < 0.001), high ratio of metastatic/total lymph nodes (p < 0.001), and high pN stage (p < 0.001). Overall survival was significantly different between an extranodal tumor extension (-) group and an extranodal tumor extension (+) group for both N1 (p = 0.022) and N2 homogeneous staging (p = 0.007). Both overall (p = 0.002) and disease-free survival (p = 0.001) were significantly different between the two groups in an N1a homogeneous group and overall survival was significantly different (p = 0.016) in an N2b homogeneous group. Conclusion. Our study demonstrated that extranodal tumor extension was a useful prognostic factor for colorectal adenocarcinoma with lymph node metastasis, especially in homogeneous pN staging groups.

Review of the touch preparation cytology of spindle epithelial tumor with thymus-like differentiation.

We experienced a case of spindle epithelial tumor with thymus-like differentiation (SETTLE) with touch preparation cytology performed during the intraoperative frozen section diagnosis in a 22-year-old woman. The tumor was partially encapsulated by fibrous capsule. It was a highly cellular biphasic tumor characterized by fasciculated spindle cells with streaming pattern and tubulopapillary epithelial component. The tumor cells were positive for cytokeratin, vimentin, c-kit, epithelial membrane antigen (EMA), and thyroid transcription factor-1 (TTF-1). However, the tumor cells were negative for thyroglobulin, calcitonin, CD99, S-100 protein, CD34, smooth muscle actin, HBME-1, and galectin-3. The reviewed touch smears showed tight clusters with high cellularity. Most cellular clusters showed papillary configuration. However, some clusters showed spindle cells with streaming pattern. The spindle tumor cells showed elongated and cigar-shaped nuclei. Although the incidence is very rare, SETLLE should be included in the differential diagnosis when a spindle cell neoplasm is encountered in touch preparation cytology in young patients with a thyroid mass.

Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast.

PURPOSE: Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen-activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. METHODS: We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. RESULTS: Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. CONCLUSION: DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer.

Immunohistochemical expression of dual-specificity protein phosphatase 4 in patients with colorectal adenocarcinoma.

The role of dual-specificity protein phosphatase 4 (DUSP4) appears to vary with the type of malignant tumors and is still controversial. The purpose of our study was to clarify the exact role of DUSP4 expression in colorectal adenocarcinoma. We constructed tissue microarrays and investigated DUSP4 expression by immunohistochemistry. DUSP4 was more frequently expressed in adenocarcinomas and lymph node/distant metastases compared to that in normal colorectal tissues and tubular adenomas (P < 0.001). Mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (P < 0.001). DUSP4 expression was significantly correlated with older age (P = 0.017), male gender (P = 0.036), larger tumor size (P = 0.014), nonmucinous tumor type (P = 0.023), and higher T stage (P = 0.040). Kaplan-Meier survival curves revealed a significant effect of DUSP4 expression on both overall survival and disease-free survival in AJCC stage I (P = 0.008 and P = 0.003, resp., log-rank test) and male gender (P = 0.017 and P = 0.049, resp., log-rank test). DUSP4 protein is frequently upregulated in colorectal adenocarcinoma and may play an important role in carcinogenesis and cancer progression and may be a marker of adverse prognosis.

Appendiceal Crohn's disease clinically presenting as acute appendicitis.

AIM: To determine the incidence of appendiceal Crohn's disease (CD) and to summarize the characteristic histologic features of appendiceal CD. METHODS: We reviewed the pathology files of 2179 appendectomy specimens from January 2007 to May 2013. The computer-assisted retrieval search facility was utilized to collect specimens. We selected those cases that were diagnosed as CD or chronic granulomatous inflammation and defined the final diagnosis according to the histologic findings of CD, including transmural lymphocytic inflammation, non-caseating epithelioid granulomas, thickening of the appendiceal wall secondary to hypertrophy of muscularis mucosa, mucosal ulceration with crypt abscesses, mucosal fissures, and fistula formation. RESULTS: We found 12 cases (7 male and 5 female patients, with an average age of 29.8 years) of appendiceal CD. The incidence of appendiceal CD was 0.55%. The chief complaints were right lower quadrant pain, abdominal pain, lower abdominal pain, and diarrhea. The duration of symptom varied from 2 d to 5 mo. The histologic review revealed appendiceal wall thickening in 11 cases (92%), transmural inflammation in all cases (100%), lymphoid aggregates in all cases (100%), epithelioid granulomas in all cases (100%), mucosal ulceration in 11 cases (92%), crypt abscesses in 5 cases (42%), perforation in 2 cases (17%), muscular hypertrophy in 1 case (8%), neural hyperplasia in 5 cases (42%), and perpendicular serosal fibrosis in 8 cases (67%). CONCLUSION: A typical and protracted clinical course, unusual gross features of the appendix and the characteristic histologic features are a clue in the diagnosis of appendiceal CD.

Splenic hamartoma: A case report and review of the literature.

Splenic hamartoma is a rare benign malformation, composed of an anomalous mixture of normal splenic elements, often found incidentally while working up other complaints or at autopsy. A splenic mass was incidentally found while evaluating the effects of a traffic accident in a 63-year-old woman. Abdominal computed tomography revealed a well-defined splenic mass with rim enhancement. The patient underwent splenectomy. The resected spleen contained a well-defined mass lesion measuring 3.5 cm × 3.0 cm. Microscopic examination revealed disorganized slit-like vascular channels lined by plump endothelial cells without atypia. The cells lining the vascular channels were positive for CD8, CD31, CD34 and vimentin. Endothelial cells that are positive for CD8 are a key feature that differentiates hamartoma from other vascular lesions of the spleen. Although this tumor is very rare, it must be included in the differential diagnosis of splenic mass-forming lesions.

Cytomegalovirus enteritis with jejunal perforation in a patient with endometrial adenocarcinoma.

Cytomegalovirus (CMV) infection of the gastrointestinal tract has been reported most frequently in the setting of immunodeficiency. The whole gastrointestinal tract can be affected; however, the small bowel is rarely affected. We report a case of CMV enteritis with jejunal perforation in a 53-year-old woman with a history of chemoradiation therapy for endometrial cancer 8 years previously. At follow-up evaluation, lower abdominal pain, diarrhea and vomiting appeared. Abdominal computed tomography showed intra-abdominal free air in the subphrenic space and porta hepatis. The jejunal segment revealed serosal purulent exudates with a perforation. The resected jejunal segment showed a large geographic ulcerative mucosal lesion. The microscopic findings revealed a diffuse ulcerative mucosal change with a prominent granulation tissue formation and many large atypical vascular endothelial cells and stromal fibroblasts with intranuclear or intracytoplasmic inclusion bodies. These cells were positive for CMV antibody. The final diagnosis was CMV-associated jejunitis with a jejunal perforation.

Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast.

AIMS: Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor involved in cell adhesion. Loss or decreased expression of CADM4 has been associated with the development and progression of some cancers. The purpose of this study was to investigate the clinicopathological significance of CADM4 expression in breast cancer. METHODS: We constructed tissue microarrays to evaluate the immunohistochemical expression of CADM4 in 256 cases of invasive ductal carcinoma (IDC) and 45 cases of ductal carcinoma in situ (DCIS). RESULTS: CADM4 was expressed in 37 (82.2%) DCIS cases, and in 173 (67.6%) IDC cases. CADM4 expression was higher in DCIS than in IDC (p=0.049). Loss or decrease of CADM4 expression was significantly correlated with higher histological grade (p=0.020), absence of oestrogen receptors (p<0.001), absence of progesterone receptors (p=0.024), and overexpression of c-erbB-2 (p=0.018). In univariable and multivariable Cox regression analyses of all 256 IDC cases, CADM4 expression was not significantly associated with overall and disease-free survival. However, it showed a significant positive association with longer disease-free survival in 187 stages I and II IDC cases (p=0.039, log-rank test). CONCLUSIONS: Loss or decrease of CADM4 expression seems to play an important role in breast cancer invasiveness, and it is associated with poorer biological parameters. CADM4 can be used as a novel marker predicting risk of recurrence and disease outcomes in stages I and II IDC.