Expression of Metabolism-Related Proteins in Lacrimal Gland Adenoid Cystic Carcinoma

Koo, Ja Seung,Yoon, Jin Sook American Society for Clinical Pathology 2015 American journal of clinical pathology Vol.143 No.4

<P><B>Objectives:</B></P><P>To investigate the expression and the clinical implications of metabolism-related proteins in lacrimal gland adenoid cystic carcinoma (ACC) in comparison with salivary gland ACC.</P><P><B>Methods:</B></P><P>Human tissue samples of lacrimal gland ACC (n = 11) and salivary gland ACC (n = 64) were analyzed. Immunochemistry was used to measure expression of proteins related to glycolysis (glucose transporter 1, hexokinase II, carbonic anhydrase IX, and monocarboxylate transporter 4 [MCT4]), glutaminolysis (glutaminase 1 [GLS1], glutamate dehydrogenase [GDH], and amino acid transporter 2 [ASCT2]), mitochondria (adenosine triphosphate [ATP] synthase, succinate dehydrogenase A [SDHA], and succinate dehydrogenase B), and glycolytic intermediate metabolism (phosphoserine phosphatase [PSPH], serine hydroxymethyl transferase 1 [SHMT1]).</P><P><B>Results:</B></P><P>GLS1 and ASCT2 were more highly expressed, and GDH, ATP synthase, and SDHA were expressed to a lesser degree in lacrimal gland ACC than in salivary gland ACC (<I>P</I> < .05). Lacrimal gland ACC showed less of a mitochondrial phenotype than did salivary gland ACC (<I>P</I> = .001). Positivity of MCT4 and PSPH was related to shorter disease-free survival, and SHMT1 was related to shorter overall survival (<I>P</I> < .05).</P><P><B>Conclusions:</B></P><P>Lacrimal gland ACC exhibited higher expression of GLS1 and ASCT2, compared with salivary gland ACC. Overexpression of MCT4, PSPH, and SHMT1 was associated with poorer prognosis.</P>

<i>HER2</i> Heterogeneity Affects Trastuzumab Responses and Survival in Patients With HER2-Positive Metastatic Breast Cancer

Lee, Hee Jin,Seo, An Na,Kim, Eun Joo,Jang, Min Hye,Suh, Koung Jin,Ryu, Han Suk,Kim, Yu Jung,Kim, Jee Hyun,Im, Seock-Ah,Gong, Gyungyub,Jung, Kyung Hae,Park, In Ae,Park, So Yeon American Society for Clinical Pathology 2014 American journal of clinical pathology Vol.142 No.6

<P><B>Objectives:</B></P><P>Heterogeneity of <I>HER2</I> gene amplification is found in a subset of breast cancers. We investigated the impact of <I>HER2</I> heterogeneity on trastuzumab responses and clinical outcomes in 112 patients with HER2-positive metastatic breast cancer.</P><P><B>Methods:</B></P><P>Regional and genetic heterogeneity of <I>HER2</I> gene amplification was determined in three different areas of each tumor by immunohistochemistry and silver in situ hybridization. We also assessed the overall levels of <I>HER2</I> amplification and the proportion of tumor cells with a <I>HER2</I>/CEP17 ratio of more than 2.2 or strong and complete membranous (3+) expression of HER2 protein.</P><P><B>Results:</B></P><P><I>HER2</I> regional and genetic heterogeneity based on the <I>HER2</I>/CEP17 ratio was confirmed in 8.7% and 2.7% of cases, respectively. Poor response to trastuzumab was associated with overall low-level or equivocal amplification, <I>HER2</I> regional heterogeneity by the <I>HER2</I>/CEP17 ratio, the <I>HER2</I>/CEP17 ratio of more than 2.2 in less than 80% of tumor cells, and <I>HER2</I> immunohistochemical expression of 3+ in less than 75% of tumor cells. In survival analyses, low-level or equivocal <I>HER2</I> amplification, <I>HER2</I> regional heterogeneity based on the <I>HER2</I>/CEP17 ratio, and the <I>HER2</I>/CEP17 ratio of more than 2.2 in less than 80% of tumor cells were associated with shorter time to progression and lower overall survival in univariate and multivariate analyses.</P><P><B>Conclusions:</B></P><P>These results suggest that accurate assessment of <I>HER2</I> status, including <I>HER2</I> heterogeneity, is important in predicting trastuzumab responses and outcomes in patients with HER2-positive metastatic breast cancer.</P>

Use of hTERT and HPV E6/E7 mRNA RT-qPCR TaqMan Assays in Combination for Diagnosing High-Grade Cervical Lesions and Malignant Tumors

Wang, Hye-Young,Park, Sunyoung,Kim, Sunghyun,Lee, Dongsup,Kim, Geehyuk,Kim, Yeun,Park, Kwang Hwa,Lee, Hyeyoung American Society for Clinical Pathology 2015 American journal of clinical pathology Vol.143 No.3

<P>Objectives: Human papillomavirus (HPV) is a major cause of cervical cancer, which is the second most common cancer in women. HPV E6 initiates degradation of cellular tumor suppressor protein p53, induces human telomerase reverse transcriptase (hTERT) activity, and then leads to progressive cervical carcinogenesis. Methods: In this study, the CervicGen HPV RT-qDX assay (Optipharm, Osong, Republic of Korea), which detects 16 HPV high-risk subtypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, and 69), and the CervicGen hTERT RT-qDX assay (Optipharm) were evaluated using 545 ThinPrep (Hologic, Bedford, MO Papanicolaou samples. Results: The positivity for the HPV E6/E7 messenger RNA (mRNA) assay was 94.4%, 95.2%, 82.4%, 46.5%, 25.0%, and 1.1% in squamous cell carcinomas, high-grade squamous intraepithelial lesions (HSILs), atypical squamous cells-cannot exclude HSIL, low-grade squamous intraepithelial lesions, atypical squamous cells of undetermined significance, and normal cytology samples, respectively. Five cervical intraepithelial neoplasia grade 2+ samples were not detected by the HPV E6/E7 mRNA assay, but they exhibited positive signals in the hTERT mRNA assay. Notably, the hTERT mRNA expression level was increased in high-grade cervical lesions but was very low in all 288 normal samples. Conclusions: These data suggest that the combination of HPV E6/E7 and hTERT mRNA expression levels could be used in a complementary manner in diagnosing high-grade cervical lesions and malignant tumors and might be useful as a predictive marker in monitoring low-grade cervical lesions.</P>

Loss of CDC14B Expression in Clear Cell Renal Cell Carcinoma : Meta-Analysis of Microarray Data Sets

Kim, Younghye,Choi, Jung-Woo,Lee, Ju-Han,Kim, Young-Sik American Society for Clinical Pathology 2014 American journal of clinical pathology Vol.141 No.4

<P><B>Objectives:</B></P><P>To discover significant differentially expressed genes (DEGs) in clear cell renal cell carcinoma (ccRCC) that might be unidentified by single microarray analysis.</P><P><B>Methods:</B></P><P>The effect sizes of five ccRCC microarray data sets were combined using a random-effects model. The most downregulated gene was validated in paired 80 ccRCC tissues by immunohistochemistry.</P><P><B>Results:</B></P><P>CDC14B was the most downregulated gene among 1,761 DEGs. CDC14B was strongly expressed in the apical proximal tubules in the nonneoplastic tissues, while it was completely absent in 10 (12.5%) of 80 or downregulated in 70 (87.5%) of 80 ccRCC cases. The complete loss of CDC14B correlated with high T stage (P = .038), advanced TNM stage (P = .027), tumor recurrence (P = .038), and shorter recurrence-free survival (P = .046) compared with the partial loss of CDC14B.</P><P><B>Conclusions:</B></P><P>Microarray meta-analysis is a useful tool for pathologists. CDC14B expression is downregulated in ccRCC, suggesting its role in renal carcinogenesis.</P>

Comparison of Prolonged Prothrombin and Activated Partial Thromboplastin Time Results With Thrombelastograph Parameters

Kim, Boram,Quan, Mei-Lian,Goh, Ri-Young,Kim, Ji-Eun,Woo, Kwang-Sook,Kim, Moo-Hyun,Han, Jin-Yeong American Society for Clinical Pathology 2013 Laboratory medicine Vol.44 No.4

<P><B>Objective:</B></P><P>The aim of this study was to investigate the performance and feasibility of the rotational thromboelastometry (ROTEM) profile by comparing prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) results with ROTEM parameters.</P><P><B>Methods:</B></P><P>We tested external TEM (EXTEM)– and internal TEM (INTEM)–activated determinations, mainly focusing on 5 basic parameters: Clotting time (CT), clot formation time (CFT), α angle, clot formation rate (CFR), and maximum clot firmness (MCF). We then compared PT and APTT results with ROTEM parameters.</P><P><B>Results:</B></P><P>We observed no significant correlations between any of the ROTEM EXTEM or INTEM parameters and PT results. Similarly, only 1 parameter, the INTEM CT value, was significantly correlated with APTT results (<I>r</I><SUP>2</SUP> = 0.165, <I>P</I> <.05).</P><P><B>Conclusion:</B></P><P>Much work is still needed to further evaluate ROTEM assay results stemming from clinical scenarios and standard laboratory testing.</P>

VE1 Antibody Is Not Highly Specific for the <i>BRAF</i> V600E Mutation in Thyroid Cytology Categories With the Exception of Malignant Cases

Lee, Sang-Ryung,Yim, Hyunee,Han, Jae Ho,Lee, Kyi Beom,Lee, Jeonghun,Soh, Euy Young,Kim, Dae Jung,Chung, Yoon-Sok,Jeong, Seon-Yong,Sheen, Seung Soo,Park, So Hyun,Kim, Jang-Hee American Society for Clinical Pathology 2015 American journal of clinical pathology Vol.143 No.3

<P><B>Objectives:</B></P><P>We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the <I>BRAF</I> V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC).</P><P><B>Methods:</B></P><P>We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the <I>BRAF</I> mutation in these specimens matched with their corresponding histology.</P><P><B>Results:</B></P><P>Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%.</P><P><B>Conclusions:</B></P><P>VE1 immunocytochemistry in thyroid FNAC as a screening test for <I>BRAF</I> mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases.</P>

Poorly Differentiated Colorectal Cancers : Correlation of Microsatellite Instability With Clinicopathologic Features and Survival

Xiao, Haitao,Yoon, Yong Sik,Hong, Seung-Mo,Roh, Seon Ae,Cho, Dong-Hyung,Yu, Chang Sik,Kim, Jin Cheon American Society for Clinical Pathology 2013 American journal of clinical pathology Vol.140 No.3

<P><B>Objectives:</B></P><P>To evaluate the association of microsatellite instability (MSI) with clinicopathologic features and oncologic outcomes in patients with poorly differentiated colorectal cancer (PD).</P><P><B>Methods:</B></P><P>Study patients were divided into well-differentiated colorectal cancer (WD) and PD, which were compared according to histologic differentiation and MSI status.</P><P><B>Results:</B></P><P>Among 1,941 patients, PD was more frequent among microsatellite-unstable tumors (23.6%) than among microsatellite-stable (MSS) tumors (4.2%, <I>P</I> < .001). Patients with PD had worse 4-year overall survival rates than patients with WD (78.6% vs 88.2%, <I>P</I> = 0.010). Compared with MSS-PD tumors, MSI-PD tumors were characterized by right-colon predilection, larger size, and infrequent lymph node metastasis (<I>P</I> < .001 to <I>P</I> = .007).</P><P><B>Conclusions:</B></P><P>The clinicopathologic characteristics of PD were closely associated with those of MSI. The outcomes of MSI-PD tumors were better than those of MSS-PD tumors, but this finding did not reach statistical significance.</P>

Unusual Expression of Thyroid Transcription Factor 1 and Napsin A in Metastatic Adenoid Cystic Carcinoma of Extrapulmonary Origin in the Lung

An, Jungsuk,Park, Sanghui,Sung, Sun Hee,Cho, Min-Sun,Kim, Seung Cheol American Society for Clinical Pathology 2014 American journal of clinical pathology Vol.141 No.5

<P><B>Objectives</B></P><P>Our study examines thyroid transcription factor 1 (TTF-1) expression in 40 primary adenoid cystic carcinomas (ACCs) arising in various sites and compares TTF-1 expression between primary and metastatic ACCs in 12 cases with distant metastases.</P><P><B>Methods</B></P><P>Forty patients with ACCs, including 12 pairs of primary and metastatic ACCs, were evaluated for the immunohistochemical expression of TTF-1 (clone SPT24). In addition, 10 metastatic ACCs to the lung were tested on napsin A and a different TTF-1 antibody (clone 8G7G3) for further evaluation.</P><P><B>Results</B></P><P>No primary ACCs showed TTF-1 immunoreactivity (clone SPT24). TTF-1 was positive in five (41.7%) of 12 metastatic ACCs; all five cases were found only in the lung and comprised five (50.0%) of 10 cases. In all positive cases, staining was focal and detected only in the cribriform histologic subtype. Staining patterns using both antibodies (both SPT24 and 8G7G3) were very similar, and TTF-1–positive tumor cells were also positive for napsin A. Extrapulmonary ACCs were all negative for TTF-1 regardless of origination and metastasis.</P><P><B>Conclusions</B></P><P>TTF-1– and napsin A–positive ACCs in the lung should not be considered primary ACCs because TTF-1 and napsin A can be expressed in metastatic ACCs of the lung.</P>

<i>FGFR2</i> Assessment in Gastric Cancer Using Quantitative Real-Time Polymerase Chain Reaction, Fluorescent In Situ Hybridization, and Immunohistochemistry

Park, Young Soo,Na, Young-Soon,Ryu, Min-Hee,Lee, Chae-Won,Park, Hye Jin,Lee, Ju-Kyung,Park, Sook Ryun,Ryoo, Baek-Yeol,Kang, Yoon-Koo American Society for Clinical Pathology 2015 American journal of clinical pathology Vol.143 No.6

<P><B>Objectives:</B></P><P>Fibroblast growth factor receptor 2 <I>(FGFR2)</I> amplification has been reported to be a target for treatment in gastric cancer. However, an optimal tissue source and method for evaluating <I>FGFR2</I> have yet to be established.</P><P><B>Methods:</B></P><P>Copy numbers were compared by quantitative polymerase chain reaction (qPCR) using frozen vs formalin-fixed, paraffin-embedded (FFPE) tissue and biopsy vs surgical specimens. We correlated the results of qPCR and immunohistochemistry (IHC) with fluorescence in situ hybridization (FISH) using stage IV gastric cancer biopsy specimens and validated the results in surgical specimens.</P><P><B>Results:</B></P><P>FFPE tissues were suitable for qPCR, and biopsy specimens were equivalent to or better than surgical specimens. qPCR and IHC results exhibited an excellent correlation with FISH at eight or more copies by qPCR in any kind of tissue, 5% or more by IHC in biopsy specimens, and 10% or more by IHC in surgical specimens. <I>FGFR2</I> amplification was 6.6% in stage IV gastric cancers, and 42% of these showed heterogeneous amplification and overexpression. IHC indicated a good correlation with FISH even in the heterogeneous cases.</P><P><B>Conclusions:</B></P><P>FFPE biopsy tissues are an adequate source for <I>FGFR2</I> evaluation in gastric carcinomas, and a qPCR-based copy number assay can be used for screening. IHC is also a valid and practical method for evaluating <I>FGFR2</I>, considering frequent heterogeneity.</P>

Traditional Serrated Adenoma of the Colorectum : Clinicopathologic Implications and Endoscopic Findings of the Precursor Lesions

Kim, Mi-Jung,Lee, Eun-Jung,Suh, Jung-Pil,Chun, Sung-Min,Jang, Se-Jin,Kim, Do Sun,Lee, Doo Han,Lee, Suk Hee,Youk, Eui Gon American Society for Clinical Pathology 2013 American journal of clinical pathology Vol.140 No.6

<P><B>Objectives:</B></P><P>To investigate the clinicopathologic and endoscopic features of precursor lesions associated with traditional serrated adenomas (TSAs).</P><P><B>Methods:</B></P><P>Mutation studies for BRAF, KRAS, PIK3CA, and EGFR and immunohistochemical staining for Ki-67 were performed on 107 TSAs from 104 patients.</P><P><B>Results:</B></P><P>Nondysplastic hyperplastic polyp (HP) or sessile serrated adenoma/polyp (SSA/P) precursor lesions were found in 56 (52.3%) TSAs, among which 32 (57.1%) cases showed a flat-elevated lesion with a type II pit pattern during endoscopy. TSAs with an SSA/P precursor lesion were usually found in the proximal colon, while TSAs with an HP or with no precursor lesion were mainly located in the distal colon and rectum (<I>P</I> < .001). TSAs with a precursor lesion showed a lower frequency of conventional epithelial dysplasia and KRAS mutation as well as a higher frequency of BRAF mutation compared with those with no precursor lesion (<I>P</I> = .002, <I>P</I> < .001, and <I>P</I> < .001, respectively).</P><P><B>Conclusions:</B></P><P>A significant proportion of HP or SSA/P precursor lesions accompanied by TSAs can be detected by endoscopy based on both their flat-elevated growth and type II pit patterns. The heterogeneity of TSAs in terms of clinicopathologic and molecular features correlated with the status or type of precursor lesions.</P>