Kyueng-Whan Min

Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma.

Jang K‐S, Song Y S, Jang S‐H, Min K‐W, Na W, Jang S M, Jun Y J, Lee K H, Choi D & Paik S S
(2010) Histopathology56, 229–239

Helicobacter pylori Infection is Associated with Elevated Low Density Lipoprotein Cholesterol Levels in Elderly Koreans

This study was conducted to investigate the association between Helicobacter pylori (H. pylori) infection and the lipid profile among elderly Koreans. A total of 462 subjects (mean age 66.2 ± 7.6 yr, 84% males) who underwent health check-up were investigated. Each subject underwent gastroduodenoscopy with gastric mucosal biopsy, and H. pylori infection was determined by histopathological examination using the updated Sydney System score. The presence of H. pylori infection was significantly associated with the elevated serum levels of total cholesterol and low density lipoprotein (LDL) cholesterol (P < 0.05 for each) in univariate analysis. H. pylori infection was not associated with triglyceride and high density lipoprotein (HDL) cholesterol levels (P > 0.05 for each). After controlling confounders, multiple logistic regression analysis showed that the odds ratio of H. pylori infection for high LDL cholesterol level (> 140 mg/dL) was 3.113 (95% confidence interval, 1.364-7.018; P = 0.007). There were no significant associations between the presence of H. pylori infection and elevated total cholesterol levels (> 200 mg/dL) in this model (P = 0.586). The results of this study demonstrate that H. pylori infection is associated with the elevated serum LDL cholesterol levels in elderly Koreans, supporting the hypothesis that H. pylori plays a role in promoting atherosclerosis by modifying lipid metabolism.

Reduced expression of Apaf-1 in colorectal adenocarcinoma correlates with tumor progression and aggressive phenotype.

BackgroundApoptotic protease activating factor-1 (Apaf-1) is one of the key regulators in the mitochondrial apoptotic pathway, and the loss of Apaf-1 leads to cellular resistance against the apoptotic signals. We investigated the expression of Apaf-1 in colorectal tissues corresponding to the multistep carcinogenesis model to determine correlations between the clinicopathologic characteristics and the expression of this molecule and to evaluate the role of Apaf-1 in the development and progression of colorectal adenocarcinoma.MethodsImmunohistochemistry for Apaf-1 was performed on the tissue microarray of 38 normal mucosal tissues, 46 adenomatous polyps, 529 colorectal adenocarcinomas, and 76 metastatic tumors.ResultsNormal colonic mucosa tissues and adenomas were positive for Apaf-1 with no exceptions (100%). However, in colorectal adenocarcinomas, 119 of 529 cases (22.5%) were positive and 410 cases (77.5%) were negative. Moreover, 67 of 76 metastatic cases (88.2 %) were negative and only nine cases (11.8%) were positive for Apaf-1 expression. In the analyses between Apaf-1 expression and clinicopathologic parameters, reduced expression of Apaf-1 correlated with left colon location (p < 0.001), deeper tumor invasion (p < 0.001), frequent lymph node metastasis ( p= 0.021), higher American Joint Committee on Cancer (AJCC) and Dukes’ stage (p = 0.02 and p = 0.001, respectively) and poorer differentiation (p < 0.001). The patient survival was significantly associated with age, histological grade, AJCC stage, and lymphovascular invasion, but not Apaf-1 expression (p = 0.478).ConclusionsThe results suggest that the loss of Apaf-1 expression is a relatively frequent late event and the loss of Apaf-1 expression may play an important role in tumorigenesis and tumor progression in colorectal adenocarcinoma.

Histopathological spectrum of cutaneous tuberculosis and non-tuberculous mycobacterial infections.

The non‐specific clinical findings and variable histopathological features of cutaneous tuberculosis and non‐tuberculous mycobacterial infections often make it difficult to establish a diagnosis and initiate appropriate therapy. We investigated 25 patients diagnosed with mycobacterial infections of the skin in Hanyang University Hospital between 2001 and 2011. Skin biopsy specimens were re‐evaluated by various histopathological criteria and molecular studies. To identify the mycobacteria, we performed staining for acid‐fast bacilli and also completed polymerase chain reaction analysis. The non‐tuberculous mycobacterium species were identified by genetic sequencing of formalin‐fixed, paraffin‐embedded tissues. Immunocompromised status was more frequent in non‐tuberculous mycobacterial infections than in tuberculosis (p = 0.017) while disease duration was longer in tuberculosis (p = 0.026). Microscopically, neutrophil infiltration, interstitial granuloma, small vessel proliferation and increased numbers of bacilli were found to be associated with non‐tuberculous mycobacterial infections (all p < 0.05). In contrast, giant cells, plasma cells, tuberculoid granulomas and necrosis were associated with tuberculosis (all p < 0.05). There were no species‐specific histopathological findings in non‐tuberculous mycobacterial infections. The significant histopathological differences between cutaneous tuberculous and non‐tuberculous mycobacterial infections are helpful in considering differential diagnoses. In addition, molecular techniques together with clinico‐pathological findings may assist in making accurate diagnoses of cutaneous non‐tuberculous mycobacterial infections.

Imaging mass spectrometry in papillary thyroid carcinoma for the identification and validation of biomarker proteins.

Direct tissue imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization and time-of-flight (MALDI-TOF) mass spectrometry has become increasingly important in biology and medicine, because this technology can detect the relative abundance and spatial distribution of interesting proteins in tissues. Five thyroid cancer samples, along with normal tissue, were sliced and transferred onto conductive glass slides. After laser scanning by MALDI-TOF equipped with a smart beam laser, images were created for individual masses and proteins were classified at 200-µm spatial resolution. Based on the spatial distribution, region-specific proteins on a tumor lesion could be identified by protein extraction from tumor tissue and analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using all the spectral data at each spot, various intensities of a specific peak were detected in the tumor and normal regions of the thyroid. Differences in the molecular weights of expressed proteins between tumor and normal regions were analyzed using unsupervised and supervised clustering. To verify the presence of discovered proteins through IMS, we identified ribosomal protein P2, which is specific for cancer. We have demonstrated the feasibility of IMS as a useful tool for the analysis of tissue sections, and identified the tumor-specific protein ribosomal protein P2. Graphical Abstract

Primary Synovial Sarcoma of the Thyroid Gland

Synovial sarcoma is a rare but distinct soft tissue neoplasm, most commonly occurring in para-articular regions of the extremities of young adults and also occurring in the head and neck region. To the best of our knowledge, only one case of primary synovial sarcoma of the thyroid has been previously reported. Here, we report a 15-yr-old man who had a chief complaint of a palpable neck mass. The neck computed tomography revealed a relatively well-demarcated solid mass in the left thyroid gland. After fine needle aspiration cytology, total thyroidectomy and lymph node dissection were performed. Grossly, the mass was covered by the same capsule as the thyroid gland, measuring 6×5×5 cm in dimensions and weighing 78 gm. The cut surface showed a well demarcated, lobulated, grayish tan, and rubbery solid tumor. Histologically, this tumor was a biphasic synovial sarcoma. Immunohistochemical, ultrastructural, genetic studies, and cytologic findings were all consistent with synovial sarcoma. When synovial sarcomas arise in this unusual site, recognition and differential diagnosis become more difficult. The differential diagnosis of a spindle epithelial tumor with thymus-like differentiation is very difficult due to their similar clinical, histological, and immunohistochemical features. Ultrastructural and cytogenetic studies for synovial sarcoma are necessary to establish a definitive diagnosis.

The Glycolytic Phenotype is Correlated with Aggressiveness and Poor Prognosis in Invasive Ductal Carcinomas

Purpose Glucose uptake and glycolytic metabolism are enhanced in cancer cells, and increased expression of glucose transporter 1 (GLUT1) has also been reported. The aim of this study was to investigate GLUT1 expression in human breast tissues and invasive ductal carcinomas. Methods We used tissue microarrays consisting of normal breast tissue, ductal hyperplasia, ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastases. We examined GLUT1 expression in the microarrays by immunohistochemistry, reviewed the medical records and performed a clinicopathological analysis. Results Membranous GLUT1 expression was observed in normal and tumor cells. GLUT1 expression was higher in ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastasis than in normal tissue and ductal hyperplasia (p=0.002). Of 276 invasive ductal carcinomas, 106 (38.4%) showed GLUT1 expression. GLUT1 expression was correlated with higher histologic grade (p<0.001), larger tumor size (p=0.025), absence of estrogen receptor (p<0.001), absence of progesterone receptor (p<0.001), and triple-negative phenotype (p<0.001). In univariate survival analysis, patients with GLUT1 expression had poorer overall survival and disease-free survival (p=0.017 and p=0.021, respectively, log-rank test). In multivariate survival analysis with the Cox proportional hazards model, GLUT1 expression was an independent prognostic factor of poorer overall survival and disease-free survival (p=0.017 and p=0.019, respectively). Conclusion GLUT1 expression seems to play an important role in malignant transformation, and the glycolytic phenotype in invasive ductal carcinoma may indicate aggressive biological behavior and a worse prognosis.

Differential Diagnosis of Lupus and Primary Membranous Nephropathies by IgG Subclass Analysis

BACKGROUND AND OBJECTIVES Previous studies showed that the accuracy of IgG subclasses (ISs) in differentiating membranous lupus nephritis (MLN) from primary membranous nephropathy (PMN) is <80%. This study hypothesized that diagnostic accuracy of ISs would be increased if renal compartment measurements and decision tree analysis are applied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Renal biopsy specimens from 41 patients with MLN and 59 patients with PMN between October 2004 and March 2010 were examined, and immunofluorescence staining against IgG1, IgG2, IgG3, and IgG4 as well as C3, C1q, and C4 was evaluated in five different renal compartments (glomerular capillary walls, mesangium, tubules, interstitium, and blood vessels). From IS data, a decision tree to differentiate MLN from PMN was produced (IS decision tree) and its accuracy was compared with that of previous studies. Diagnostic accuracy of the IS decision tree was also compared with that of the complement decision tree as a reference. RESULTS The demographic information and patterns of IS deposition were similar to those of previous studies. The IS decision tree had, as decision markers, IgG1 in the mesangium and IgG2 and IgG4 along the glomerular capillary wall. The IS decision tree showed higher accuracy (88%) than that of previous studies (<80%) and also that of the complement decision tree (81%). CONCLUSIONS Accuracy of ISs was increased due to the study methods, but the same methodology was less effective using complement measurements. Appropriate data analysis may enhance diagnostic value, but the analysis alone cannot achieve the ideal diagnostic value.

ERG Immunohistochemistry as an Endothelial Marker for Assessing Lymphovascular Invasion

Background ERG, a member of the ETS family of transcription factors, is a highly specific endothelial marker. We investigated whether the use of ERG immunostaining can help pathologists detect lymphovascular invasion (LVI) and decrease interobserver variability in LVI diagnosis. Methods Fifteen cases of surgically resected colorectal cancers with hepatic metastasis were selected and the most representative sections for LVI detection were immunostained with ERG, CD31, and D2-40. Eight pathologists independently evaluated LVI status on hematoxylin and eosin (H&E) and the corresponding immunostained sections and then convened for a consensus meeting. The results were analyzed by kappa (κ) statistics. Results The average rate of LVI positivity was observed in 43% with H&E only, 10% with CD31, 29% with D2-40, and 16% with ERG. Agreement among pathologists was fair for H&E only (κ=0.27), D2-40 (κ=0.21), ERG (κ=0.23), and was moderate for CD31 (κ=0.55). Consensus revealed that ERG nuclear immunoreactivity showed better visual contrast of LVI detection than the other staining, with improved agreement and LVI detection rate (κ=0.65, LVI positivity rate 80%). Conclusions The present study demonstrated a superiority with ERG immunostaining and indicated that ERG is a promising panendothelial marker that might help pathologists increase LVI detection and decrease interobserver variability in LVI diagnosis.

Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas

Aims Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor. The purpose of this study was to investigate the correlation between its expression and the expression of E-cadherin and Ki-67 in colorectal adenocarcinomas, as well as its effect on patient survival. Methods We evaluated CADM4 expression in tissue microarrays of 513 colorectal adenocarcinomas by immunohistochemistry. Results CADM4 was highly expressed in 210 of the 513 colorectal adenocarcinomas; expression was reduced in 185 cases and absent in the remaining cases. Loss of CADM4 expression was correlated with larger tumour size (6.2±2.1 cm vs 5.3±2.0 cm, p<0.001), mucinous tumour type (61.5% vs 20.9%, p<0.001), lymph node metastasis (31.4% vs 20.9%, p=0.022), higher Dukes stage (25.5% vs 19.6%, p=0.044), poorer differentiation (38.5% vs 18.8%, p<0.001), absence of E-cadherin expression (28.5% vs 16.0%, p=0.007) and presence of Ki-67 expression (27.3% vs 12.3%, p<0.001). In univariable Cox regression analysis, absence of CADM4 expression was associated with poorer overall survival (HR 0.712; 95% CI 0.512 to 0.989, p=0.042) and disease-free survival (HR 0.732; 95% CI 0.546 to 0.981, p=0.037). In multivariate analysis with the Cox proportional hazards model, CADM4 expression was not an independent prognostic factor of overall survival (HR 0.726; 95% CI 0.516 to 1.021, p=0.066) and disease-free survival (HR 0.762; 95% CI 0.563 to 1.033, p=0.080). Conclusions Loss of CADM4 expression is relatively frequent in colorectal adenocarcinomas and may play an important role in cancer progression and patient survival.