Hyung Kyu Park

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.

Duodenal Gangliocytic Paraganglioma With Lymph Node Metastasis

Gangliocytic paraganglioma is a rare tumor that occurs most commonly in the second portion of the duodenum. It is characterized by its triphasic cellular differentiation: epithelioid neuroendocrine cells, spindle cells with Schwann cell differentiation, and ganglion cells. Most gangliocytic paragangliomas are considered benign and are amenable to local excision. However, to our knowledge, 23 cases with lymph node metastasis have been reported, 1 case of bone metastasis, and 2 cases of liver metastases. Predictive factors that have been suggested for lymph node metastasis include size (larger than 2 cm), young age, and tumors exceeding the submucosal layer. Our objective was to review the clinical features, the histopathologic characteristics, and the differential diagnosis of gangliocytic paraganglioma and to discuss the value of the predictive factors for lymph node metastasis.

Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer

EGFR and KRAS mutations are two of the most common mutations that are present in lung cancer. Screening and detecting these mutations are of issue these days, and many different methods and tissue samples are currently used to effectively detect these two mutations. In this study, we aimed to evaluate the testing for EGFR and KRAS mutations by pyrosequencing method, and compared the yield of cytology versus histology specimens in a consecutive series of patients with lung cancer. We retrospectively reviewed EGFR and KRAS mutation results of 399 (patients with EGFR mutation test) and 323 patients (patients with KRAS mutation test) diagnosed with lung cancer in Konkuk University Medical Center from 2008 to 2014. Among them, 60 patients had received both EGFR and KRAS mutation studies. We compared the detection rate of EGFR and KRAS tests in cytology, biopsy, and resection specimens. EGFR and KRAS mutations were detected in 29.8% and 8.7% of total patients, and the positive mutation results of EGFR and KRAS were mutually exclusive. The detection rate of EGFR mutation in cytology was higher than non-cytology (biopsy or resection) materials (cytology: 48.5%, non-cytology: 26.1%), and the detection rate of KRAS mutation in cytology specimens was comparable to non-cytology specimens (cytology: 8.3%, non-cytology: 8.7%). We suggest that cytology specimens are good alternatives that can readily substitute tissue samples for testing both EGFR and KRAS mutations. Moreover, pyrosequencing method is highly sensitive in detecting EGFR and KRAS mutations in lung cancer patients.

Clinical Significance of Substaging and HER2 Expression in Papillary Nonmuscle Invasive Urothelial Cancers of the Urinary Bladder

The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC. Graphical Abstract

Expression of Peroxisome Proliferator Activated Receptor gamma in Prostatic Adenocarcinoma

Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer. Graphical Abstract

Unforeseen clonal evolution of tumor cell population in recurrent and metastatic dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma, generally of low-grade malignancy. DFSP is locally aggressive with a high recurrence rate, but metastasis occurs rarely. To investigate the mechanism of metastasis in DFSP, we analyzed the whole exome sequencing data of serial tumor samples obtained from a patient who had a 10-year history of recurrent and metastatic DFSP. Tracking various genomic alterations, namely somatic mutations, copy number variations, and chromosomal rearrangements, we observed a dramatic change in tumor cell population during the occurrence of metastasis in this DFSP case. The new subclone that emerged in metastatic DFSP harbored a completely different set of somatic mutations and new focal amplifications, which had not been observed in the primary clone before metastasis. The COL1A1-PDGFB fusion, characteristic of DFSP, was found in all of the serial samples. Moreover, the break position on the fusion gene was identical in all samples. Based on these observations, we suggest a clonal evolution model to explain the mechanism underlying metastasis in DFSP and identified several candidate target genes responsible for metastatic DFSP by utilizing The Cancer Genome Atlas database. This is the first study to observe clonal evolution in metastatic DFSP and provide insight for a possible therapeutic strategy for imatinib-resistant or metastatic DFSP.

Mixed Carcinoma as an Independent Prognostic Factor in Submucosal Invasive Gastric Carcinoma

Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005–2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma.

Primary Ductal Adenocarcinoma of the Lacrimal Gland, associated with Abundant Intracytoplasmic Lumens containing Some Eosinophilic Hyaline Globules: Cytological, Histological and Ultrastructural Findings

Abstract A primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare distinct subtype of an epithelial tumor arising in the lacrimal gland. PDA is the counterpart of salivary duct carcinoma (SDC) resembling an invasive ductal carcinoma (IDC) of the breast. In our case, PDA revealed histopathological and immunohistochemical results corresponding to SDC. Interestingly, the tumor cells showed intracytoplasmic vacuoles containing dense eosinophilic hyaline globules at light microscopy. Ultrastructurally, the tumor cells exhibited microvilli-lined intracytoplasmic lumen containing homogenous electron-dense secretory products. A previous study demonstrated that numerous intracytoplasmic lumens of tumor cells are favored breast malignant tumor, similar to the histopathology of PDA, rather than benign lesion. This characteristic finding may be meaningful to diagnose high grade epithelial tumors including PDA.

Pancreatic Ductal Adenocarcinoma: Rim Enhancement at MR Imaging Predicts Prognosis after Curative Resection

Purpose To identify features at preoperative magnetic resonance (MR) imaging that could predict favorable prognosis after curative resection of pancreatic ductal adenocarcinoma (PDAC). Materials and Methods From January 2009 to December 2014, this retrospective study included 143 patients with surgically resected (ie, R0) PDAC who underwent preoperative MR imaging within 1 month before surgery. Clinical-pathologic and MR imaging findings for predicting disease-free survival (DFS) and overall survival (OS) were identified by using a Cox proportional hazards model. Important MR imaging features were compared with clinical-pathologic findings. Results Tumor size at histopathologic analysis was associated with both DFS and OS (hazard ratio per centimeter, 1.37; 95% confidence interval: 1.15, 1.63; P < .001 and hazard ratio, 1.44; 95% confidence interval: 1.20, 1.73; P < .001, respectively). Rim enhancement at dynamic contrast material-enhanced MR imaging was associated with significantly worse DFS and OS (hazard ratio, 1.72; 95% confidence interval: 1.05, 2.82; P = .030 and hazard ratio, 2.27; 95% confidence interval: 1.39, 3.69; P = .001, respectively). Diffusion-weighted imaging parameters, including diffusion restriction and apparent diffusion coefficient value, did not predict DFS or OS after resection of PDAC (all P > .05). Rim-enhancing lesions had more aggressive histologic tumor grades, less frequent remaining acini, and more frequent necrosis within the tumor compared with non-rim-enhancing pancreatic lesions (P = .002, P = .008, and P < .001, respectively). Conclusion Greater tumor size and rim enhancement were associated with lower DFS and OS rates after attempted curative resection of PDAC.

Comparison and evaluation of risk factors for meningeal, pleural, and extrapleural solitary fibrous tumors: A clinicopathological study of 92 cases confirmed by STAT6 immunohistochemical staining

Solitary fibrous tumors (SFTs) are an uncommon type of mesenchymal tumors that are presumably fibroblastic in nature. SFTs are translocation-associated neoplasms that can be consistently diagnosed through the evaluation of NAB2/STAT6 gene fusion. Currently, SFTs have a different grading system and criteria according to their primary sites, and the differences and similarities in SFTs according to their primary sites are still poorly understood. Therefore, we compared SFTs according to their primary sites and histologic appearance, and validated the current grading system of SFTs. A total of 92 patients (with 15 meningeal, 40 pleural, and 37 extrapleural SFTs) were evaluated. The patients with pleural SFTs (mean age: 60.2 years) showed a significantly increased age at diagnosis. Tumors with hemangiopericytoma-predominant morphology had significantly higher grades in the evaluation of several risk factors such as cellularity (P<0.001), pleomorphism (P=0.001), and mitotic activity (P<0.001). Consequently, hemangiopericytoma (HPC)-predominant tumors had a significantly higher recurrence rate. The meningeal SFT group had significantly higher proportion of the HPC-predominant histologic phenotype compared with pleural or extrapleural SFTs (66.67% vs. 5.00% or 18.92%, respectively; P<0.001). Consequently, meningeal SFTs showed significantly higher recurrence rates compared with pleural or extrapleural SFTs (33.33% vs. 12.50% or 2.70%, respectively; P=0.009). Regarding the evaluation of risk factors, a tumor size ≥10cm (P=0.017), a mitotic index ≥4/10 high power fields (HPFs) (P=0.001), high tumor cellularity (P=0.003), high nuclear pleomorphism (P=0.005), and tumor necrosis (P=0.004) were associated with both recurrence and disease-specific mortality. Upon evaluation of the usefulness of the criteria using previously described factors, the predictive model was on the borderline of validation. Of the five factors indicated in the log rank test, only a mitotic index ≥4/10 HPFs remained a significant factor in the multivariate Cox model.