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Immunohistochemistry for Pathologists: Protocols, Pitfalls, and Tips
So-Woon Kim, Jin Roh, Chan-Sik Park
J Pathol Transl Med. 2016;50(6):411-418.   Published online October 13, 2016
DOI: https://doi.org/10.4132/jptm.2016.08.08
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AbstractAbstract PDF
Immunohistochemistry (IHC) is an important auxiliary method for pathologists in routine diagnostic work as well as in basic and clinical research including exploration of biomarkers, as IHC allows confirmation of target molecule expressions in the context of microenvironment. Although there has been a considerable progress in automation and standardization of IHC, there are still many things to be considered in proper optimization and appropriate interpretation. In this review, we aim to provide possible pitfalls and useful tips for practicing pathologists and residents in pathology training. First, general procedure of IHC is summarized, followed by pitfalls and tips in each step and a summary of troubleshooting. Second, ways to an accurate interpretation of IHC are discussed, with introduction to general quantification and analysis methods. This review is not intended to provide complete information on IHC, but to be used as a basic reference for practice and publication.

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Article image
HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation
Soomin Ahn, Ji Won Woo, Kyoungyul Lee, So Yeon Park
J Pathol Transl Med. 2020;54(1):34-44.   Published online November 6, 2019
DOI: https://doi.org/10.4132/jptm.2019.11.03
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AbstractAbstract PDF
Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals may lead to inaccurate assessment of HER2 status. Moreover, HER2 status can be altered after neoadjuvant chemotherapy or during metastatic progression, due to biologic or methodologic issues. This review addresses recent updates of ASCO/CAP guidelines and factors complicating in the interpretation of HER2 status in breast cancers.

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    Pathology - Research and Practice.2024; 262: 155550.     CrossRef
  • Systematic review of added immunotherapy in traditional treatment for HER2 positive breast cancer patients
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  • Detecting early-stage breast cancer with GATA3-positive circulating tumor cells
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    Taiwanese Journal of Obstetrics and Gynecology.2024; 63(5): 745.     CrossRef
  • First-in-human study of DP303c, a HER2-targeted antibody-drug conjugate in patients with HER2 positive solid tumors
    Jian Zhang, Yiqun Du, Yanchun Meng, Xiaojun Liu, Yuxin Mu, Yunpeng Liu, Yehui Shi, Jufeng Wang, Aimin Zang, Shanzhi Gu, Tianshu Liu, Huan Zhou, Hongqian Guo, Silong Xiang, Xialu Zhang, Suqiong Wu, Huanhuan Qi, Mengke Li, Xichun Hu
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  • Targeting CD276 for T cell-based immunotherapy of breast cancer
    Ilona Hagelstein, Laura Wessling, Alexander Rochwarger, Latifa Zekri, Boris Klimovich, Christian M. Tegeler, Gundram Jung, Christian M. Schürch, Helmut R. Salih, Martina S. Lutz
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  • Correlation of Androgen Receptor Expression With Ki67 Proliferative Index and Other Clinicopathological Characteristics in Invasive Mammary Carcinomas
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  • MicroRNAs and their role in breast cancer metabolism (Review)
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  • CDH1 methylation and expression of E-cadherin and other markers in breast cancer
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  • Determining HER2 Status by Artificial Intelligence: An Investigation of Primary, Metastatic, and HER2 Low Breast Tumors
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  • Gene amplification mutations originate prior to selective stress in Acinetobacter baylyi
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  • Protective Effect of HER2 Gene Polymorphism rs24537331 in the Outcome of Canine Mammary Tumors
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    Breast Cancer: Targets and Therapy.2023; Volume 15: 281.     CrossRef
  • HER2 Low Breast Cancer: A New Subtype or a Trojan for Cytotoxic Drug Delivery?
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  • Histopathological and immunohistochemical analysis of predictive and prognostic markers in spontaneous canine mammary cancer
    Vladimír Tancoš, Marcel Kovalik, Martin Levkut, Martina Bobrovská, Petra Kolenčíková, Ľubomír Straka, Zuzana Ševčíková, Ondřej Škor, Martina Antošová, Lukáš Plank, Keith L. Thoday
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  • Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study
    Timothy Qi, Yanguang Cao
    European Journal of Pharmaceutical Sciences.2023; 186: 106467.     CrossRef
  • The Effect of HER2-Low Status on Pathological Complete Response and Survival in Triple-Negative Breast Cancer: A Systemic Review and Meta-Analysis
    Yakup Ergun, Baran Akagunduz, Cengiz Karacin, Sema Turker, Gokhan Ucar
    Clinical Breast Cancer.2023; 23(6): 567.     CrossRef
  • Efficacy, toxicity and prognostic factors of pyrotinib‑involved neoadjuvant therapy in HER2‑positive breast cancer: A retrospective study
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  • Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer
    Feng Ye, Saikat Dewanjee, Yuehua Li, Niraj Kumar Jha, Zhe-Sheng Chen, Ankush Kumar, Vishakha, Tapan Behl, Saurabh Kumar Jha, Hailin Tang
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  • Weakly supervised bilayer convolutional network in segmentation of HER2 related cells to guide HER2 targeted therapies
    Ching-Wei Wang, Kun-Lin Lin, Hikam Muzakky, Yi-Jia Lin, Tai-Kuang Chao
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  • Immune Biomarkers in Triple-Negative Breast Cancer: Improving the Predictivity of Current Testing Methods
    Francesca Maria Porta, Elham Sajjadi, Konstantinos Venetis, Chiara Frascarelli, Giulia Cursano, Elena Guerini-Rocco, Nicola Fusco, Mariia Ivanova
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  • HER2 Equivocal (Score = 2+) Breast Carcinoma Cases Identified by Immunohistochemistry at a South African Hospital. What is the Impact of Fluorescent In Situ Hybridization Testing?
    Reena Dhansukh Mohanlal, Nikki Bouwer, Pascale Willem
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  • Discordance of HER2 Expression and/or Amplification on Repeat Testing
    Timothy P. DiPeri, Kathleen Kong, Kaushik Varadarajan, Daniel D. Karp, Jaffer A. Ajani, Shubham Pant, Michael F. Press, Sarina A. Piha-Paul, Ecaterina E. Dumbrava, Funda Meric-Bernstam
    Molecular Cancer Therapeutics.2023; 22(8): 976.     CrossRef
  • Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes
    Mariausilia Franchina, Cristina Pizzimenti, Vincenzo Fiorentino, Maurizio Martini, Giuseppina Rosaria Rita Ricciardi, Nicola Silvestris, Antonio Ieni, Giovanni Tuccari
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  • Genetic analysis of oligo-recurrence breast cancer: correlation with clinical outcomes
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  • Single domain antibodies specific for HER2 dimerization domain effectively disrupts HER2 dimerization
    Ahmad Najafi, Reza Valadan, Hossein Asgarian-Omran, Alireza Rafiei, Mohsen Tehrani
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  • Récepteur du facteur de croissance épidermique HER2, tests utilisés pour rechercher son amplification dans le cancer du sein : principes et limites
    Imane Eliahiai, Mohammed Eljiar, Sanae Chaib, Jinane KHarmoum, Mariame Chraïbi
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  • Integrated Molecular Characterization of HER2-Low Breast Cancer Using Next Generation Sequencing (NGS)
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  • GLUCOSE LEVELS OF PLEURAL EFFUSION FLUID AND HER2 STATUS IN PLEURAL-METASTATIC BREAST CANCER
    Muhammad Dhanny Irawan, Desak Gede Agung Suprabawati, Heru Purwanto
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  • Design of a Ratiometric Plasmonic Biosensor for Herceptin Detection in HER2-Positive Breast Cancer
    Neda Shahbazi, Rouholah Zare-Dorabei, Seyed Morteza Naghib
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  • A highly sensitive nanobiosensor based on aptamer-conjugated graphene-decorated rhodium nanoparticles for detection of HER2-positive circulating tumor cells
    Mahdi Sadeghi, Soheila Kashanian, Seyed Morteza Naghib, Esfandyar Askari, Fateme Haghiralsadat, Davood Tofighi
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    Carrie S. Wynn, Shou-Ching Tang
    Cancer and Metastasis Reviews.2022; 41(1): 193.     CrossRef
  • Electroanalytical overview: screen-printed electrochemical sensing platforms for the detection of vital cardiac, cancer and inflammatory biomarkers
    Robert D. Crapnell, Alejandro Garcia-Miranda Ferrari, Nina C. Dempsey, Craig E. Banks
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  • FTO genotype was associated with breast cancer in HER2 negative patients
    Fateme Montazeri, Hossein Hatami, Soroor Fathi, Naeemeh Hasanpour Ardekanizadeh, Fatemeh Bourbour, Samira Rastgoo, Fatemeh Shafiee, Mohammad Esmail Akbari, Maryam Gholamalizadeh, Seyed Alireza Mosavi Jarrahi, Saeid Doaei
    Clinical Nutrition ESPEN.2022; 49: 495.     CrossRef
  • Breast Cancer Human Epidermal Growth Factor Receptor 2 mRNA Molecular Testing Compared to Immunohistochemistry with Correlation to Neoadjuvant Therapy Response
    Mahmoud Behairy, Samia Mohamed Gabal, Mohamed Sherif Negm
    Open Access Macedonian Journal of Medical Sciences.2022; 10(A): 352.     CrossRef
  • Validity and utility of HER2/ERBB2 copy number variation assessed in liquid biopsies from breast cancer patients: A systematic review
    Noortje Verschoor, Teoman Deger, Agnes Jager, Stefan Sleijfer, Saskia M. Wilting, John W.M. Martens
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  • RETRACTED: Longitude Variation of the microRNA-497/FGF-23 Axis during Treatment and Its Linkage with Neoadjuvant/Adjuvant Trastuzumab-Induced Cardiotoxicity in HER2-Positive Breast Cancer Patients
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  • Use of Radionuclide-Based Imaging Methods in Breast Cancer
    Betül Altunay, Agnieszka Morgenroth, Felix M. Mottaghy
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  • Functional regulations between genetic alteration-driven genes and drug target genes acting as prognostic biomarkers in breast cancer
    Li Wang, Lei Yu, Jian Shi, Feng Li, Caiyu Zhang, Haotian Xu, Xiangzhe Yin, Lixia Wang, Shihua Lin, Anastasiia Litvinova, Yanyan Ping, Shangwei Ning, Hongying Zhao
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    Anastasia Alataki, Mitch Dowsett
    Endocrine-Related Cancer.2022; 29(8): R105.     CrossRef
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    Olga D. Bragina, Sergei M. Deyev, Vladimir I. Chernov, Vladimir M. Tolmachev
    Acta Naturae.2022; 14(2): 4.     CrossRef
  • Deriving tumor purity from cancer next generation sequencing data: applications for quantitative ERBB2 (HER2) copy number analysis and germline inference of BRCA1 and BRCA2 mutations
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  • Current challenges and unmet needs in treating patients with human epidermal growth factor receptor 2-positive advanced breast cancer
    Matti Aapro, Fatima Cardoso, Giuseppe Curigliano, Alexandru Eniu, Joseph Gligorov, Nadia Harbeck, Andreas Mueller, Olivia Pagani, Shani Paluch-Shimon, Elzbieta Senkus, Beat Thürlimann, Khalil Zaman
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  • [Retracted] Application of Fluorescence In Situ Hybridization Assisted by Fluorescence Microscope in Detection of Her2 Gene in Breast Cancer Patients
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  • Indian Data on HER2 Fluorescence In Situ Hybridization in Invasive Breast Cancer with Immunohistochemically Equivocal Results As Per 2018 ASCO/CAP Guidelines
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  • S‑phase fraction, lymph node status and disease staging as the main prognostic factors to differentiate between young and older patients with invasive breast carcinoma
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  • Clinical possibilities of HER2-positive breast cancer diagnosis using alternative scaffold proteins
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    Bulletin of Siberian Medicine.2022; 21(3): 132.     CrossRef
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  • Loss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion
    Julien Ablain, Amira Al Mahi, Harriet Rothschild, Meera Prasad, Sophie Aires, Song Yang, Maxim E. Dokukin, Shuyun Xu, Michelle Dang, Igor Sokolov, Christine G. Lian, Leonard I. Zon
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  • An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low)
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  • Development of T-cell engagers selective for cells co-expressing two antigens
    Danielle M. Dicara, Sunil Bhakta, Mary Ann Go, James Ziai, Ron Firestein, Bill Forrest, Chen Gu, Steven R. Leong, Genee Lee, Shang-Fan Yu, Andrew G. Polson, Nicholas J. Agard
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  • Antibody-Drug Conjugates in Breast Cancer: Spotlight on HER2
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  • The Clinical Utility of Droplet Digital PCR for Profiling Circulating Tumor DNA in Breast Cancer Patients
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    Diagnostics.2022; 12(12): 3042.     CrossRef
  • Lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy for HER2 positive breast cancer patients: an updated systematic review and meta-analysis
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  • Interactions dietary components with expression level of breast cancer-related genes
    Fatemeh Bourbour, Azam Pourtaheri, Khadijeh Abbasi, Naeemeh Hasanpour Ardekanizadeh, Maryam Gholamalizadeh, Azadeh Hajipour, Sepideh Abdollahi, Seyedeh Elaheh Bagheri, Mina Ahmadzadeh, Saeid Doaei, Arezoo Haghighian
    Egyptian Journal of Medical Human Genetics.2022;[Epub]     CrossRef
  • HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging
    Betül Altunay, Agnieszka Morgenroth, Mohsen Beheshti, Andreas Vogg, Nicholas C. L. Wong, Hong Hoi Ting, Hans-Jürgen Biersack, Elmar Stickeler, Felix M. Mottaghy
    European Journal of Nuclear Medicine and Molecular Imaging.2021; 48(5): 1371.     CrossRef
  • Risk-based decision-making in the treatment of HER2-positive early breast cancer: Recommendations based on the current state of knowledge
    Christian Jackisch, Patricia Cortazar, Charles E. Geyer, Luca Gianni, Joseph Gligorov, Zuzana Machackova, Edith A. Perez, Andreas Schneeweiss, Sara M. Tolaney, Michael Untch, Andrew Wardley, Martine Piccart
    Cancer Treatment Reviews.2021; 99: 102229.     CrossRef
  • Histologic Patterns of Cutaneous Metastases of Breast Carcinoma: A Clinicopathologic Study of 232 Cases
    Shira Ronen, David Suster, Wei-Shen Chen, Natali Ronen, Sri Krishna C. Arudra, Celestine Trinidad, Doina Ivan, Victor G. Prieto, Saul Suster
    The American Journal of Dermatopathology.2021; 43(6): 401.     CrossRef
  • Standardized pathology report for breast cancer
    Soo Youn Cho, So Yeon Park, Young Kyung Bae, Jee Yeon Kim, Eun Kyung Kim, Woo Gyeong Kim, Youngmee Kwon, Ahwon Lee, Hee Jin Lee, Ji Shin Lee, Jee Young Park, Gyungyub Gong, Hye Kyoung Yoon
    Journal of Pathology and Translational Medicine.2021; 55(1): 1.     CrossRef
  • The impact of oral contraceptive use on breast cancer risk: State of the art and future perspectives in the era of 4P medicine
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  • The Co-Expression of Melanoma-Antigen Family a Proteins and New York Esophageal Squamous Cell Carcinoma-1 in Breast Cancer: A Pilot Study
    Yu-Xin Wang, Feng-Lian Li, Li-Xin Du, Jun-Fang Liu, Li-Gang Huo, Shu-Qing Li, Bin Tian
    Cancer Management and Research.2021; Volume 13: 6123.     CrossRef
  • Targeting HER2 protein in individual cells using ICP-MS detection and its potential as prognostic and predictive breast cancer biomarker
    A. Fernández Asensio, M. Corte-Rodríguez, J. Bettmer, L.M. Sierra, M. Montes-Bayón, E. Blanco- González
    Talanta.2021; 235: 122773.     CrossRef
  • Development of a 99mTc-Labeled Single-Domain Antibody for SPECT/CT Assessment of HER2 Expression in Breast Cancer
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  • WITHDRAWN: Nouvelles stratégies thérapeutiques dans les cancers du sein HER2-surexprimé
    Benoîte Mery, Philippe Toussaint, Pierre-Etienne Heudel, Armelle Dufresne, Mélodie Carbonnaux, Hélène Vanacker, Thomas Bachelot, Olivier Trédan
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  • Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases
    Emad A. Rakha, Islam M. Miligy, Cecily M. Quinn, Elena Provenzano, Abeer M. Shaaban, Caterina Marchiò, Michael S. Toss, Grace Gallagy, Ciara Murray, Janice Walshe, Ayaka Katayama, Karim Eldib, Nahla Badr, Bruce Tanchel, Rebecca Millican-Slater, Colin Purd
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  • Loss of HER2‐positivity following neoadjuvant targeted therapy for breast cancer is not associated with inferior oncologic outcomes
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  • Clinical and Genetic Predictive Models for the Prediction of Pathological Complete Response to Optimize the Effectiveness for Trastuzumab Based Chemotherapy
    Lun Li, Min Chen, Shuyue Zheng, Hanlu Li, Weiru Chi, Bingqiu Xiu, Qi Zhang, Jianjing Hou, Jia Wang, Jiong Wu
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  • tRNA‐derived fragments: tRF‐Gly‐CCC‐046, tRF‐Tyr‐GTA‐010 and tRF‐Pro‐TGG‐001 as novel diagnostic biomarkers for breast cancer
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  • Detection of secondary metastatic breast cancer by measurement of plasma CA 15.3
    L. De Cock, J. Heylen, A. Wildiers, K. Punie, A. Smeets, C. Weltens, P. Neven, J. Billen, A. Laenen, H. Wildiers
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Original Article
Cancers with Higher Density of Tumor-Associated Macrophages Were Associated with Poor Survival Rates
Kyong Yeun Jung, Sun Wook Cho, Young A Kim, Daein Kim, Byung-Chul Oh, Do Joon Park, Young Joo Park
J Pathol Transl Med. 2015;49(4):318-324.   Published online June 17, 2015
DOI: https://doi.org/10.4132/jptm.2015.06.01
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AbstractAbstract PDF
Background
Macrophages are a component of a tumor’s microenvironment and have various roles in tumor progression and metastasis. This study evaluated the relationships between tumor-associated macrophage (TAM) density and clinical outcomes in 14 different types of human cancers. Methods: We investigated TAM density in human tissue microarray sections from 14 different types of human cancers (n = 266) and normal thyroid, lung, and breast tissues (n = 22). The five-year survival rates of each cancer were obtained from the 2011 Korea Central Cancer Registry. Results: Among 13 human cancers, excluding thyroid cancer, pancreas, lung, and gallbladder cancers had the highest density of CD163-positive macrophages (7.0±3.5%, 6.9±7.4%, and 6.9 ± 5.5%, respectively). The five-year relative survival rates of these cancers (pancreas, 8.7%; lung, 20.7%; gallbladder, 27.5%) were lower than those of other cancers. The histological subtypes in thyroid cancer exhibited significantly different CD163-positive macrophages densities (papillary, 1.8 ± 1.6% vs anaplastic, 22.9 ± 17.1%; p < .001), but no significant difference between histological subtypes was detected in lung and breast cancers. Moreover, there was no significant difference in CD163-positive macrophages densities among the TNM stages in lung, breast, and thyroid cancers. Conclusions: Cancers with higher TAM densities (pancreas, lung, anaplastic thyroid, and gallbladder) were associated with poor survival rate.

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Reviews
Artificial Intelligence in Pathology
Hye Yoon Chang, Chan Kwon Jung, Junwoo Isaac Woo, Sanghun Lee, Joonyoung Cho, Sun Woo Kim, Tae-Yeong Kwak
J Pathol Transl Med. 2019;53(1):1-12.   Published online December 28, 2018
DOI: https://doi.org/10.4132/jptm.2018.12.16
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AbstractAbstract PDF
As in other domains, artificial intelligence is becoming increasingly important in medicine. In particular,deep learning-based pattern recognition methods can advance the field of pathology byincorporating clinical, radiologic, and genomic data to accurately diagnose diseases and predictpatient prognoses. In this review, we present an overview of artificial intelligence, the brief historyof artificial intelligence in the medical domain, recent advances in artificial intelligence applied topathology, and future prospects of pathology driven by artificial intelligence.

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Pathology Reporting of Thyroid Core Needle Biopsy: A Proposal of the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group
Chan Kwon Jung, Hye Sook Min, Hyo Jin Park, Dong Eun Song, Jang Hee Kim, So Yeon Park, Hyunju Yoo, Mi Kyung Shin, Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group
J Pathol Transl Med. 2015;49(4):288-299.   Published online June 17, 2015
DOI: https://doi.org/10.4132/jptm.2015.06.04
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AbstractAbstract PDF
In recent years throughout Korea, the use of ultrasound-guided core needle biopsy (CNB) has become common for the preoperative diagnosis of thyroid nodules. However, there is no consensus on the pathology reporting system for thyroid CNB. The Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group held a conference on thyroid CNB pathology and developed guidelines through contributions from the participants. This article discusses the outcome of the discussions that led to a consensus on the pathology reporting of thyroid CNB.

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Article image
Introduction to digital pathology and computer-aided pathology
Soojeong Nam, Yosep Chong, Chan Kwon Jung, Tae-Yeong Kwak, Ji Youl Lee, Jihwan Park, Mi Jung Rho, Heounjeong Go
J Pathol Transl Med. 2020;54(2):125-134.   Published online February 13, 2020
DOI: https://doi.org/10.4132/jptm.2019.12.31
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AbstractAbstract PDF
Digital pathology (DP) is no longer an unfamiliar term for pathologists, but it is still difficult for many pathologists to understand the engineering and mathematics concepts involved in DP. Computer-aided pathology (CAP) aids pathologists in diagnosis. However, some consider CAP a threat to the existence of pathologists and are skeptical of its clinical utility. Implementation of DP is very burdensome for pathologists because technical factors, impact on workflow, and information technology infrastructure must be considered. In this paper, various terms related to DP and computer-aided pathologic diagnosis are defined, current applications of DP are discussed, and various issues related to implementation of DP are outlined. The development of computer-aided pathologic diagnostic tools and their limitations are also discussed.

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Original Articles
Accuracy of Core Needle Biopsy Versus Fine Needle Aspiration Cytology for Diagnosing Salivary Gland Tumors
In Hye Song, Joon Seon Song, Chang Ohk Sung, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim, Jeong Hyun Lee, Jung Hwan Baek, Kyung-Ja Cho
J Pathol Transl Med. 2015;49(2):136-143.   Published online March 12, 2015
DOI: https://doi.org/10.4132/jptm.2015.01.03
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AbstractAbstract PDF
Background
Core needle biopsy is a relatively new technique used to diagnose salivary gland lesions, and its role in comparison with fine needle aspiration cytology needs to be refined. Methods: We compared the results of 228 ultrasound-guided core needle biopsy and 371 fine needle aspiration procedures performed on major salivary gland tumors with their postoperative histological diagnoses. Results: Core needle biopsy resulted in significantly higher sensitivity and more accurate tumor subtyping, especially for malignant tumors, than fine needle aspiration. No patient developed major complications after core needle biopsy. Conclusions: We recommend ultrasoundguided core needle biopsy as the primary diagnostic tool for the preoperative evaluation of patients with salivary gland lesions, especially when malignancy is suspected.

Citations

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Microsatellite Instability Status in Gastric Cancer: A Reappraisal of Its Clinical Significance and Relationship with Mucin Phenotypes
Joo-Yeun Kim, Na Ri Shin, Ahrong Kim, Hyun-Jeong Lee, Won-young Park, Jee-Yeon Kim, Chang-Hun Lee, Gi-Young Huh, Do Youn Park
Korean J Pathol. 2013;47(1):28-35.   Published online February 25, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.28
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AbstractAbstract PDF
Background

Gastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear.

Methods

MSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed.

Results

Out of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197).

Conclusions

Our data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.

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Finding and Characterizing Mammary Analogue Secretory Carcinoma of the Salivary Gland
Min Jung Jung, Joon Seon Song, Sang Yoon Kim, Soon Yuhl Nam, Jong-Lyel Roh, Seung-Ho Choi, Sung-Bae Kim, Kyung-Ja Cho
Korean J Pathol. 2013;47(1):36-43.   Published online February 25, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.36
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AbstractAbstract PDF
Background

A new tumor entity of the salivary glands, mammary analogue secretory carcinoma (MASC) with ETV6-NTRK3 translocation, has recently been proposed. MASC was originally diagnosed as adenocarcinoma, not otherwise specified (ANOS), or acinic cell carcinoma (AciCC) by the current World Health Organization classification. We aimed to identify MASC cases by molecular tests, and to characterize their clinical, histological, and immunohistochemical features.

Methods

Thirty cases of MASC candidates were selected after review of 196 salivary gland tumors, and subjected to break-apart ETV6 fluorescence in situ hybridization (FISH), and immunohistochemical study for S100 protein, gross cystic disease fluid protein 15, DOG1, estrogen receptor, and progesterone receptor.

Results

Valid FISH results were obtained in 23 cases, and 13 positive cases were retrieved. MASCs were histologically varied, and the most frequent features observed in 10 cases were low-grade papillary/cystic/glandular patterns, intraluminal secretory materials, ovoid/wrinkled nuclei, and relatively abundant granular eosinophilic cytoplasms, corresponding to papillary-cystic or follicular types of AciCC. All cases showed diffuse immunopositivity for S100 protein. Three cases developed recurrences, but all patients remained alive.

Conclusions

MASC could be a molecularly well-defined salivary gland neoplasm, encompassing some portions of AciCC and ANOS, but its histological spectrum and clinical implication require further investigation.

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WHO Classification of Malignant Lymphomas in Korea: Report of the Third Nationwide Study.
Jin Man Kim, Young Hyeh Ko, Seung Sook Lee, Jooryung Huh, Chang Suk Kang, Chul Woo Kim, Yun Kyung Kang, Jai Hyang Go, Min Kyung Kim, Wan Seop Kim, Yoon Jung Kim, Hyun Jung Kim, Hee Kyung Kim, Jong Hee Nam, Hyung Bae Moon, Chan Kum Park, Tae In Park, Young Ha Oh, Dong Wha Lee, Jong Sil Lee, Juhie Lee, Hyekyung Lee, Sung Chul Lim, Kyu Yun Jang, Hee Kyung Chang, Yoon Kyung Jeon, Hye Ra Jung, Min Sun Cho, Hee Jeong Cha, Suk Jin Choi, Jae Ho Han, Sook Hee Hong, Insun Kim
Korean J Pathol. 2011;45(3):254-260.
DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.3.254
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AbstractAbstract PDF
BACKGROUND
The aim of study was to determine the relative frequency of malignant lymphoma according to World Health Organization (WHO) classification in Korea.
METHODS
A total of 3,998 cases diagnosed at 31 institutes between 2005 and 2006 were enrolled. Information including age, gender, pathologic diagnosis, site of involvement and immunophenotypes were obtained.
RESULTS
The relative frequency of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) was 95.4% and 4.6%, respectively. B-cell lymphomas accounted for 77.6% of all NHL, while T/natural killer (T/NK)-cell lymphomas accounted for 22.4%. The most frequent subtypes of NHL were diffuse large B-cell lymphoma (42.7%), extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (19.0%), NK/T-cell lymphoma (6.3%) and peripheral T-cell lymphoma (PTCL), unspecified (6.3%), in decreasing order. The relative frequency of HL was nodular sclerosis (47.4%), mixed cellularity (30.6%), and nodular lymphocyte predominant (12.1%) subtypes. Compared with a previous study in 1998, increase in gastric MZBCL and nodular sclerosis HL, and slight decrease of follicular lymphoma, PTCL, and NK/T-cell lymphoma were observed.
CONCLUSIONS
Korea had lower rates of HL and follicular lymphoma, and higher rates of extranodal NHL, extranodal MZBCL, and NK/T-cell lymphoma of nasal type compared with Western countries. Changes in the relative frequency of lymphoma subtypes are likely ascribed to refined diagnostic criteria and a change in national health care policy.

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Reviews
PD-L1 Testing in Non-small Cell Lung Cancer: Past, Present, and Future
Hyojin Kim, Jin-Haeng Chung
J Pathol Transl Med. 2019;53(4):199-206.   Published online May 2, 2019
DOI: https://doi.org/10.4132/jptm.2019.04.24
Correction in: J Pathol Transl Med 2020;54(2):196
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AbstractAbstract PDF
Blockade of the programmed cell death-1 (PD-1) axis has already been established as an effective treatment of non-small cell lung cancer. Immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) protein is the only available biomarker that can guide treatment with immune checkpoint inhibitors in non-small cell lung cancer. Because each PD-1/PD-L1 blockade was approved together with a specific PD-L1 IHC assay used in the clinical trials, pathologists have been challenged with performing various assays with a limited sample. To provide a more unified understanding of this, several cross-validation studies between platforms have been performed and showed consistent results. However, the interchangeability of assays may be limited in practice because of the risk of misclassification of patients for the treatment. Furthermore, several issues, including the temporal and spatial heterogeneity of PD-L1 expression in the tumor, and the potential for cytology specimens to be used as an alternative to tissue samples for PD-L1 testing, have still not been resolved. In the future, one of the main aims of immunotherapy research should be to find a novel predictive biomarker for PD-1 blockade therapy and a way to combine it with PD-L1 IHC and other tests.

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Extracellular Vesicles and the Promise of Continuous Liquid Biopsies
Don Armstrong, Derek E. Wildman
J Pathol Transl Med. 2018;52(1):1-8.   Published online January 15, 2018
DOI: https://doi.org/10.4132/jptm.2017.05.21
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AbstractAbstract PDF
The rapid and accurate diagnosis of patients with minimally invasive procedures was once only found in science fiction. However, the discovery of extracellular vesicles (EVs) and their near ubiquity in body fluids, coupled with the advent of inexpensive next generation sequencing techniques and EV purification protocols, promises to make science fiction a reality. Purifying and sequencing the RNA content of EV from routine blood draws and urine samples are likely to enable pathologists and physicians to diagnose and track the progress of diseases in many inaccessible tissues in the near future. Here we present the evolutionary background of EV, summarize the biology of EV formation and cargo selection, and discuss the current barriers to making continuous liquid biopsies through the use of EV a science reality.

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Article image
Tumor immune response and immunotherapy in gastric cancer
Yoonjin Kwak, An Na Seo, Hee Eun Lee, Hye Seung Lee
J Pathol Transl Med. 2020;54(1):20-33.   Published online November 1, 2019
DOI: https://doi.org/10.4132/jptm.2019.10.08
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AbstractAbstract PDF
Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.

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Epstein-Barr Virus–Associated Lymphoproliferative Disorders: Review and Update on 2016 WHO Classification
Hyun-Jung Kim, Young Hyeh Ko, Ji Eun Kim, Seung-Sook Lee, Hyekyung Lee, Gyeongsin Park, Jin Ho Paik, Hee Jeong Cha, Yoo-Duk Choi, Jae Ho Han, Jooryung Huh
J Pathol Transl Med. 2017;51(4):352-358.   Published online June 5, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.15
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AbstractAbstract PDF
Epstein-Barr virus (human herpesvirus-4) is very common virus that can be detected in more than 95% of the human population. Most people are asymptomatic and live their entire lives in a chronically infected state (IgG positive). However, in some populations, the Epstein-Barr virus (EBV) has been involved in the occurrence of a wide range of B-cell lymphoproliferative disorders (LPDs), including Burkitt lymphoma, classic Hodgkin’s lymphoma, and immune–deficiency associated LPDs (post-transplant and human immunodeficiency virus–associated LPDs). T-cell LPDs have been reported to be associated with EBV with a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphomas, extranodal nasal natural killer/T-cell lymphomas, and other rare histotypes. This article reviews the current evidence covering EBV-associated LPDs based on the 2016 classification of the World Health Organization. These LPD entities often pose diagnostic challenges, both clinically and pathologically, so it is important to understand their unique pathophysiology for correct diagnoses and optimal management.

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Original Articles
Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases
Taebum Lee, Boram Lee, Yoon-La Choi, Joungho Han, Myung-Ju Ahn, Sang-Won Um
J Pathol Transl Med. 2016;50(3):197-203.   Published online April 18, 2016
DOI: https://doi.org/10.4132/jptm.2016.03.09
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  • 65 Crossref
AbstractAbstract PDF
Background
Although epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) were thought to be mutually exclusive, some tumors harbor concomitant mutations. Discovering a driver mutation on the basis of morphologic features and therapeutic responses with mutation analysis can be used to understand pathogenesis and predict resistance in targeted therapy.
Methods
In 6,637 patients with NSCLC, 12 patients who had concomitant mutations were selected and clinicopathologic features were reviewed. Clinical characteristics included sex, age, smoking history, previous treatment, and targeted therapy with response and disease-free survival. Histologic features included dominant patterns, nuclear and cytoplasmic features.
Results
All patients were diagnosed with adenocarcinoma and had an EGFR mutation. Six patients had concomitant KRAS mutations and the other six had ALK mutations. Five of six EGFR-KRAS mutation patients showed papillary and acinar histologic patterns with hobnail cells. Three of six received EGFR tyrosine kinase inhibitor (TKI) and showed partial response for 7–29 months. All six EGFR-ALK mutation patients showed solid or cribriform patterns and three had signet ring cells. Five of six EGFR-ALK mutation patients received EGFR TKI and/or ALK inhibitor and four showed partial response or stable disease, except for one patient who had acquired an EGFR mutation.
Conclusions
EGFR and ALK mutations play an important role as driver mutations in double mutated NSCLC, and morphologic analysis can be used to predict treatment response.

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Loss of E-cadherin and Acquisition of Vimentin in Epithelial-Mesenchymal Transition are Noble Indicators of Uterine Cervix Cancer Progression
Na-Hye Myong
Korean J Pathol. 2012;46(4):341-348.   Published online August 23, 2012
DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.4.341
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AbstractAbstract PDF
Background

Epithelial-mesenchymal transition (EMT) has been known to play a key role in the stromal invasion of carcinoma in situ (CIS) lesion. Loss of E-cadherin and acquisition of vimentin are two critical steps in EMT, that are induced by Snail-1 upregulation associated with overexpression of epidermal growth factor receptor (EGFR). However, roles of EMT-related proteins in human cervical tissues have not been fully elucidated. In this study, we investigated the immunoexpressions of EMT-related proteins in CIS, microinvasive squamous cell carcinoma (SCC), and invasive SCC to demonstrate their key roles in tumor progression.

Methods

Eighty one CIS, 17 microinvasive, and 21 invasive SCC cases were immunostained with primary antibodies for Snail-1, EGFR, E-cadherin, and vimentin on paraffin-embedded tissue microarray blocks.

Results

EGFR and Snail-1 proteins were highly expressed but the levels were not significantly different between the three groups. However, loss of E-cadherin and acquisition of vimentin were proven to occur significantly higher in microinvasive and invasive SCC cases than in CIS.

Conclusions

E-cadherin and vimentin were found to be two useful indicators of EMT in evaluating stromal invasion of CIS. However, it was not demonstrated for Snail-1 and EGFR proteins to play any key role in the progression of cervix cancer.

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Proposal of an Appropriate Decalcification Method of Bone Marrow Biopsy Specimens in the Era of Expanding Genetic Molecular Study
Sung-Eun Choi, Soon Won Hong, Sun Och Yoon
J Pathol Transl Med. 2015;49(3):236-242.   Published online May 15, 2015
DOI: https://doi.org/10.4132/jptm.2015.03.16
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AbstractAbstract PDF
Background
The conventional method for decalcification of bone specimens uses hydrochloric acid (HCl) and is notorious for damaging cellular RNA, DNA, and proteins, thus complicating molecular and immunohistochemical analyses. A method that can effectively decalcify while preserving genetic material is necessary. Methods: Pairs of bilateral bone marrow biopsies sampled from 53 patients were decalcified according to protocols of two comparison groups: EDTA versus HCl and RDO GOLD (RDO) versus HCl. Pairs of right and left bone marrow biopsy samples harvested from 28 cases were allocated into the EDTA versus HCl comparison group, and 25 cases to the RDO versus HCl comparison group. The decalcification protocols were compared with regards to histomorphology, immunohistochemistry, and molecular analysis. For molecular analysis, we randomly selected 5 cases from the EDTA versus HCl and RDO versus HCl groups. Results: The decalcification time for appropriate histomorphologic analysis was the longest in the EDTA method and the shortest in the RDO method. EDTA was superior to RDO or HCl in DNA yield and integrity, assessed via DNA extraction, polymerase chain reaction, and silver in situ hybridization using DNA probes. The EDTA method maintained intact nuclear protein staining on immunohistochemistry, while the HCl method produced poor quality images. Staining after the RDO method had equivocal results. RNA in situ hybridization using kappa and lambda RNA probes measured RNA integrity; the EDTA and RDO method had the best quality, followed by HCl. Conclusions: The EDTA protocol would be the best in preserving genetic material. RDO may be an acceptable alternative when rapid decalcification is necessary.

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Reviews
Article image
Molecular characteristics of meningiomas
Young Suk Lee, Youn Soo Lee
J Pathol Transl Med. 2020;54(1):45-63.   Published online January 15, 2020
DOI: https://doi.org/10.4132/jptm.2019.11.05
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AbstractAbstract PDF
Meningioma is the most common primary intracranial tumor in adults. The grading of meningioma is based on World Health Organization criteria, which rely on histopathological features alone. This grading system is unable to conclusively predict the clinical behavior of these tumors (i.e., recurrence or prognosis in benign or atypical grades). Advances in molecular techniques over the last decade that include genomic and epigenomic data associated with meningiomas have been used to identify genetic biomarkers that can predict tumor behavior. This review summarizes the molecular characteristics of meningioma using genetic and epigenetic biomarkers. Molecular alterations that can predict meningioma behavior may be integrated into the upcoming World Health Organization grading system.

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Galectins: Double-edged Swords in the Cross-roads of Pregnancy Complications and Female Reproductive Tract Inflammation and Neoplasia
Nandor Gabor Than, Roberto Romero, Andrea Balogh, Eva Karpati, Salvatore Andrea Mastrolia, Orna Staretz-Chacham, Sinuhe Hahn, Offer Erez, Zoltan Papp, Chong Jai Kim
J Pathol Transl Med. 2015;49(3):181-208.   Published online May 15, 2015
DOI: https://doi.org/10.4132/jptm.2015.02.25
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AbstractAbstract PDF
Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes.

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Article image
Molecular Testing for Gastrointestinal Cancer
Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y. Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho
J Pathol Transl Med. 2017;51(2):103-121.   Published online February 19, 2017
DOI: https://doi.org/10.4132/jptm.2017.01.24
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AbstractAbstract PDF
With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

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Article image
2019 Practice guidelines for thyroid core needle biopsy: a report of the Clinical Practice Guidelines Development Committee of the Korean Thyroid Association
Chan Kwon Jung, Jung Hwan Baek, Dong Gyu Na, Young Lyun Oh, Ka Hee Yi, Ho-Cheol Kang
J Pathol Transl Med. 2020;54(1):64-86.   Published online January 15, 2020
DOI: https://doi.org/10.4132/jptm.2019.12.04
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AbstractAbstract PDF
Ultrasound-guided core needle biopsy (CNB) has been increasingly used for the pre-operative diagnosis of thyroid nodules. Since the Korean Society of the Thyroid Radiology published the ‘Consensus Statement and Recommendations for Thyroid CNB’ in 2017 and the Korean Endocrine Pathology Thyroid CNB Study Group published ‘Pathology Reporting of Thyroid Core Needle Biopsy’ in 2015, advances have occurred rapidly not only in the management guidelines for thyroid nodules but also in the diagnostic terminology and classification schemes. The Clinical Practice Guidelines Development Committee of the Korean Thyroid Association (KTA) reviewed publications on thyroid CNB from 1995 to September 2019 and updated the recommendations and statements for the diagnosis and management of thyroid nodules using CNB. Recommendations for the resolution of clinical controversies regarding the use of CNB were based on expert opinion. These practical guidelines include recommendations and statements regarding indications for CNB, patient preparation, CNB technique, biopsy-related complications, biopsy specimen preparation and processing, and pathology interpretation and reporting of thyroid CNB.

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Original Articles
Prognostic Impact of Fusobacterium nucleatum Depends on Combined Tumor Location and Microsatellite Instability Status in Stage II/III Colorectal Cancers Treated with Adjuvant Chemotherapy
Hyeon Jeong Oh, Jung Ho Kim, Jeong Mo Bae, Hyun Jung Kim, Nam-Yun Cho, Gyeong Hoon Kang
J Pathol Transl Med. 2019;53(1):40-49.   Published online December 26, 2018
DOI: https://doi.org/10.4132/jptm.2018.11.29
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AbstractAbstract PDFSupplementary Material
Background
This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy.
Methods
F. nucleatumDNA was quantitatively measured in a total of 593 CRC tissues retrospectively collectedfrom surgically resected specimens of stage III or high-risk stage II CRC patients who had receivedcurative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOXor CAPOX). Each case was classified into one of the three categories: F. nucleatum–high, –low, or –negative.
Results
No significant differences in survival were observed between the F.nucleatum–high and –low/negative groups in the 593 CRCs (p = .671). Subgroup analyses accordingto tumor location demonstrated that disease-free survival was significantly better in F.nucleatum–high than in –low/negative patients with non-sigmoid colon cancer (including cecal,ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariateanalysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoidcolon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore,the favorable prognostic effect of F. nucleatum–high was observed only in a non-microsatellite instability-high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not ina MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor locationand MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treatedwith adjuvant chemotherapy.
Conclusions
Intratumoral F. nucleatum load is a potential prognosticfactor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treatedwith oxaliplatin-based adjuvant chemotherapy.

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Transformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases
Soomin Ahn, Soo Hyun Hwang, Joungho Han, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn, Woong-Yang Park
J Pathol Transl Med. 2016;50(4):258-263.   Published online May 10, 2016
DOI: https://doi.org/10.4132/jptm.2016.04.19
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AbstractAbstract PDF
Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first line treatment for a subset of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Although transformation to small cell lung cancer (SCLC) is one of the known mechanisms of resistance to EGFR TKIs, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors.
Methods
We identified six patients with primary lung adenocarcinoma that showed transformation to SCLC on second biopsy (n = 401) during a 6-year period. Clinicopathologic information was analyzed and EGFR mutation results were compared between initial and second biopsy samples.
Results
Six patients showed transformation from adenocarcinoma to SCLC, of which four were pure SCLCs and two were combined adenocarcinoma and SCLCs. Clinically, four cases were EGFR-mutant tumors from non-smoking females who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The remaining two adenocarcinomas were EGFR wild-type, and one of these patients received EGFR TKI treatment.
Conclusions
NSCLC can acquire a neuroendocrine phenotype with or without EGFR TKI treatment.

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Reviews
Effectiveness and Limitations of Core Needle Biopsy in the Diagnosis of Thyroid Nodules: Review of Current Literature
Jung Hyun Yoon, Eun-Kyung Kim, Jin Young Kwak, Hee Jung Moon
J Pathol Transl Med. 2015;49(3):230-235.   Published online May 15, 2015
DOI: https://doi.org/10.4132/jptm.2015.03.21
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AbstractAbstract PDF
Fine needle aspiration (FNA) is currently accepted as an easy, safe, and reliable tool for the diagnosis of thyroid nodules. Nonetheless, a proportion of FNA samples are categorized into non-diagnostic or indeterminate cytology, which frustrates both the clinician and patient. To overcome this limitation of FNA, core needle biopsy (CNB) of the thyroid has been proposed as an additional diagnostic method for more accurate and decisive diagnosis for thyroid nodules of concern. In this review, we focus on the effectiveness and limitations of CNB, and what factors should be considered when CNB is utilized in the diagnosis of thyroid nodules.

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Pathogenesis of Focal Segmental Glomerulosclerosis
Beom Jin Lim, Jae Won Yang, Woo Sung Do, Agnes B. Fogo
J Pathol Transl Med. 2016;50(6):405-410.   Published online October 16, 2016
DOI: https://doi.org/10.4132/jptm.2016.09.21
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AbstractAbstract PDF
Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

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Original Article
Eosinophils in Colorectal Neoplasms Associated with Expression of CCL11 and CCL24
Hyuck Cho, Sung-Jig Lim, Kyu Yeoun Won, Go Eun Bae, Gou Young Kim, Ji Won Min, Byeong-joo Noh
J Pathol Transl Med. 2016;50(1):45-51.   Published online December 14, 2015
DOI: https://doi.org/10.4132/jptm.2015.10.16
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AbstractAbstract PDF
Background
A decrease in the number of tissue eosinophils is known to reflect the malignancy potential of neoplastic lesions and even prognosis. Increased levels of the chemokines CCL11 and CCL24 in serum and tissue are also known to have diagnostic value as serum tumor markers or prognostic factors. The aim of this study was to evaluate the correlation between the degree of tissue eosinophilia and the expression of these chemokines in the glandular and stromal cells of colorectal neoplastic lesions ranging from benign to malignant tumors. Methods: We counted the number of infiltrating eosinophils in neoplastic lesion tissue and we evaluated the expression of CCL11 and CCL24 in glandular cells and stromal cells by immunohistochemical staining. Results: The results showed that the number of eosinophils decreased significantly and the expression of CCL11 and CCL24 in glandular cells decreased with tumor progression, whereas the stromal expression of CCL11 and CCL24 appeared to increase. Conclusions: The discrepancy in CCL11 and CCL24 expression between glandular cells and stromal cells might shed light on how colorectal cancer evades the immune system, which would enable further development of immunotherapies that target these chemokines. Further research on eosinophil biology and the expression pattern of chemokines in tumor cells is needed.

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Review
A Review of Inflammatory Processes of the Breast with a Focus on Diagnosis in Core Biopsy Samples
Timothy M. D’Alfonso, Paula S. Ginter, Sandra J. Shin
J Pathol Transl Med. 2015;49(4):279-287.   Published online June 22, 2015
DOI: https://doi.org/10.4132/jptm.2015.06.11
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AbstractAbstract PDF
Inflammatory and reactive lesions of the breast are relatively uncommon among benign breast lesions and can be the source of an abnormality on imaging. Such lesions can simulate a malignant process, based on both clinical and radiographic findings, and core biopsy is often performed to rule out malignancy. Furthermore, some inflammatory processes can mimic carcinoma or other malignancy microscopically, and vice versa. Diagnostic difficulty may arise due to the small and fragmented sample of a core biopsy. This review will focus on the pertinent clinical, radiographic, and histopathologic features of the more commonly encountered inflammatory lesions of the breast that can be characterized in a core biopsy sample. These include fat necrosis, mammary duct ectasia, granulomatous lobular mastitis, diabetic mastopathy, and abscess. The microscopic differential diagnoses for these lesions when seen in a core biopsy sample will be discussed.

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Original Articles
SIRT1 Expression Is Associated with Good Prognosis in Colorectal Cancer
Wonkyung Jung, Kwang Dae Hong, Woon Yong Jung, Eunjung Lee, Bong Kyung Shin, Han Kyeom Kim, Aeree Kim, Baek-hui Kim
Korean J Pathol. 2013;47(4):332-339.   Published online August 26, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.4.332
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AbstractAbstract PDF
Background

Silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent deacetylase, might act as a tumor promoter by inhibiting p53, but may also as a tumor suppressor by inhibiting several oncogenes such as β-catenin and survivin. Deleted in breast cancer 1 (DBC1) is known as a negative regulator of SIRT1.

Methods

Immunohistochemical expressions of SIRT1, DBC1, β-catenin, surviving, and p53 were evaluated using 2 mm tumor cores from 349 colorectal cancer patients for tissue microarray.

Results

Overexpression of SIRT1, DBC1, survivin, and p53 was seen in 235 (67%), 183 (52%), 193 (55%), and 190 (54%) patients, respectively. Altered expression of β-catenin was identified in 246 (70%) patients. On univariate analysis, overexpression of SIRT1 (p=0.029) and altered expression of β-catenin (p=0.008) were significantly associated with longer overall survival. Expression of SIRT1 was significantly related to DBC1 (p=0.001), β-catenin (p=0.001), and survivin (p=0.002), but not with p53. On multivariate analysis, age, tumor stage, differentiation, and expression of SIRT1 were independent prognostic factors significantly associated with overall survival.

Conclusions

SIRT1 overexpression is a good prognostic factor for colorectal cancer, and SIRT1 may interact with β-catenin and survivin rather than p53.

Citations

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Overexpression of POSTN in Tumor Stroma Is a Poor Prognostic Indicator of Colorectal Cancer
Hyeon Jeong Oh, Jeong Mo Bae, Xian-Yu Wen, Nam-Yun Cho, Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2017;51(3):306-313.   Published online April 12, 2017
DOI: https://doi.org/10.4132/jptm.2017.01.19
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AbstractAbstract PDF
Background
Tumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients.
Methods
We analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features.
Results
High level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival.
Conclusions
Our findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.

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Review
Molecular Testing of Brain Tumor
Sung-Hye Park, Jaekyung Won, Seong-Ik Kim, Yujin Lee, Chul-Kee Park, Seung-Ki Kim, Seung-Hong Choi
J Pathol Transl Med. 2017;51(3):205-223.   Published online May 12, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.08
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AbstractAbstract PDF
The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors.

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Original Articles
Article image
Morphological and Functional Changes in the Thyroid Follicles of the Aged Murine and Humans
Junguee Lee, Shinae Yi, Yea Eun Kang, Hyeon-Woo Kim, Kyong Hye Joung, Hae Joung Sul, Koon Soon Kim, Minho Shong
J Pathol Transl Med. 2016;50(6):426-435.   Published online October 14, 2016
DOI: https://doi.org/10.4132/jptm.2016.07.19
  • 18,085 View
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AbstractAbstract PDF
Background
Although both thyroid histology and serum concentrations of hormones are known to change with age, only a few reports exist on the relationship between the age-related structural and functional changes of the thyroid follicles in both mice and humans. Our objectives were to investigate age-related histological changes of the thyroid follicles and to determine whether these morphological changes were associated with the functional activity of the follicles.
Methods
The thyroid glands of mice at 18 weeks and at 6, 15, and 30 months of age were histologically examined, and the serum levels of thyroid hormones were measured in 11-week-old and 20-month-old mice. Samples of human thyroid tissue from 10 women over 70 years old and 10 women between 30 and 50 years of age were analyzed in conjunction with serum thyroid hormone level.
Results
The histological and functional changes observed in the thyroid follicles of aged mice and women were as follows: variable sizing and enlargement of the follicles; increased irregularity of follicles; Sanderson’s polsters in the wall of large follicles; a large thyroglobulin (Tg) globule or numerous small fragmented Tg globules in follicular lumens; oncocytic change in follicular cells; and markedly dilated follicles empty of colloid. Serum T3 levels in 20-month-old mice and humans were unremarkable.
Conclusions
Thyroid follicles of aged mice and women show characteristic morphological changes, such as cystic atrophy, empty colloid, and Tg globules.

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Effects of Fixation and Storage of Human Tissue Samples on Nucleic Acid Preservation
Soo Kyung Nam, Joon Im, Yoonjin Kwak, Nayoung Han, Kyung Han Nam, An Na Seo, Hye Seung Lee
Korean J Pathol. 2014;48(1):36-42.   Published online February 25, 2014
DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.1.36
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AbstractAbstract PDF
Background

Because of recent advances in the molecular diagnosis of cancer patients, tissue quality has become more important in daily practice.

Methods

To evaluate the effects of fixative, duration of fixation, decalcification, and storage periods on nucleic acid integrity, DNA and RNA were extracted from gastrointestinal cancer tissue. The yield and purity were analyzed, and polymerase chain reaction (PCR) for glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 60 bp), β-actin (148 bp), and human growth hormone (hGH; 434 bp) and real-time reverse transcription-PCR for β-actin (97 bp) were performed.

Results

All formalin-fixed paraffin-embedded (FFPE) and methacarn-fixed paraffin-embedded (MFPE) samples tested positive for GAPDH and β-actin by PCR. hGH was successfully detected in all MFPE samples, but in only 46.7% of the FFPE samples. Prolonged formalin fixation resulted in fewer GAPDH and β-actin PCR products, and amplification of hGH was not successful. The PCR and reverse transcription-PCR results were significantly affected by the duration of decalcification. The yield, purity, and integrity of mRNA progressively decreased with increased storage periods of paraffin blocks.

Conclusions

Fixation and storage should therefore be standardized in order to improve the quality of molecular pathologic diagnosis.

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Review
Current Concepts and Occurrence of Epithelial Odontogenic Tumors: I. Ameloblastoma and Adenomatoid Odontogenic Tumor
Suk Keun Lee, Yeon Sook Kim
Korean J Pathol. 2013;47(3):191-202.   Published online June 25, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.3.191
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AbstractAbstract PDF

Ameloblastomas and adenomatoid odontogenic tumors (AOTs) are common epithelial tumors of odontogenic origin. Ameloblastomas are clinico-pathologically classified into solid/multicystic, unicystic, desmoplastic, and peripheral types, and also divided into follicular, plexiform, acanthomatous, granular types, etc., based on their histological features. Craniopharyngiomas, derived from the remnants of Rathke's pouch or a misplaced enamel organ, are also comparable to the odontogenic tumors. The malignant transformation of ameloblastomas results in the formation of ameloblastic carcinomas and malignant ameloblastomas depending on cytological dysplasia and metastasis, respectively. AOTs are classified into follicular, extrafollicular, and peripheral types. Ameloblastomas are common, have an aggressive behavior and recurrent course, and are rarely metastatic, while AOTs are hamartomatous benign lesions derived from the complex system of the dental lamina or its remnants. With advances in the elucidation of molecular signaling mechanisms in cells, the cytodifferentiation of epithelial tumor cells in ameloblastomas and AOTs can be identified using different biomarkers. Therefore, it is suggested that comprehensive pathological observation including molecular genetic information can provide a more reliable differential diagnosis for the propagation and prognosis of ameloblastomas and AOTs. This study aimed to review the current concepts of ameloblastomas and AOTs and to discuss their clinico-pathological features relevant to tumorigenesis and prognosis.

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Original Articles
Classic Papillary Thyroid Carcinoma with Tall Cell Features and Tall Cell Variant Have Similar Clinicopathologic Features
Woo Jin Oh, Young Sub Lee, Uiju Cho, Ja Seong Bae, Sohee Lee, Min Hee Kim, Dong Jun Lim, Gyeong Sin Park, Youn Soo Lee, Chan Kwon Jung
Korean J Pathol. 2014;48(3):201-208.   Published online June 26, 2014
DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.3.201
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AbstractAbstract PDF
Background

The tall cell variant of papillary thyroid carcinoma (TCVPTC) is more aggressive than classic papillary thyroid carcinoma (PTC), but the percentage of tall cells needed to diagnose TCVPTC remains controversial. In addition, little is known about the clinicopathologic features of classic PTC with tall cell features (TCF).

Methods

We retrospectively selected and reviewed the clinicopathologic features and presence of the BRAF mutation in 203 cases of classic PTC, 149 cases of classic PTC with TCF, and 95 cases of TCVPTCs, which were defined as PTCs having <10%, 10-50%, and ≥50% tall cells, respectively.

Results

TCVPTCs and classic PTCs with TCF did not vary significantly in clinicopathologic characteristics such as pathologic (p) T stage, extrathyroidal extension, pN stage, lateral lymph node metastasis, or BRAF mutations; however, these features differed significantly in TCVPTCs and classic PTCs with TCF in comparison to classic PTCs. Similar results were obtained in a subanalysis of patients with microcarcinomas (≤1.0 cm in size).

Conclusions

Classic PTCs with TCF showed a similar BRAF mutation rate and clinicopathologic features to TCVPTCs, but more aggressive characteristics than classic PTCs.

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Incidence and Malignancy Rates of Diagnoses in the Bethesda System for Reporting Thyroid Aspiration Cytology: An Institutional Experience
Ji Hye Park, Sun Och Yoon, Eun Ju Son, Hye Min Kim, Ji Hae Nahm, SoonWon Hong
Korean J Pathol. 2014;48(2):133-139.   Published online April 28, 2014
DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.2.133
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AbstractAbstract PDF
Background

The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) uses six diagnostic categories to standardize communication of thyroid fine-needle aspiration (FNA) interpretations between clinicians and cytopathologists. Since several studies have questioned the diagnostic accuracy of this system, we examined its accuracy in our hospital.

Methods

We calculated the incidences and malignancy rates of each diagnostic category in the BSRTC for 1,730 FNAs that were interpreted by four cytopathologists in Gangnam Severance Hospital between October 1, 2011, and December 31, 2011.

Results

The diagnostic incidences of categories I-VI were as follows: 13.3%, 40.6%, 9.1%, 0.4%, 19.3%, and 17.3%, respectively. Similarly, the malignancy rates of these categories were as follows: 35.3%, 5.6%, 69.0%, 50.0%, 98.7%, and 98.9%, respectively. In categories II, V, and VI, there were no statistically significant differences in the ranges of the malignancy rates among the four cytopathologists. However, there were significant differences in the ranges for categories I and III.

Conclusions

Our findings suggest that institutions that use the BSRTC should regularly update their diagnostic criteria. We also propose that institutions issue an annual report of incidences and malignancy rates to help other clinicians improve the case management of patients with thyroid nodules.

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The Expression of CD10 and CD15 Is Progressively Increased during Colorectal Cancer Development
Tae Jung Jang, Jeong Bae Park, Jong Im Lee
Korean J Pathol. 2013;47(4):340-347.   Published online August 26, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.4.340
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AbstractAbstract PDF
Background

The aim of this study was to examine the expression of CD10 and CD15 in tumor cells, stromal cells and infiltrating inflammatory cells during colorectal carcinoma (CRC) development and to investigate their expression levels between the tumor center and invasive front and compare them to clinicopathological parameters in invasive CRC.

Methods

We performed immunohistochemical staining for CD10, CD15, and E-cadherin in 42 cases of CRC, 49 of tubular adenoma, 15 of hyperplastic polyp, and 17 of non-neoplastic colon.

Results

CD10 was expressed in tumor cells (tCD10), stromal cells (sCD10) and infiltrating inflammatory cells (iCD10), and CD15 was expressed in tumor cells (tCD15) and infiltrating inflammatory cells (iCD15). Their expressions were progressively increased during CRC development and the iCD10 expression level was significantly correlated with the iCD15 expression level in invasive CRC. Invasive front revealed a higher expression level of iCD10 and iCD15 than the tumor center. Moreover, the iCD15 expression level of invasive front was significantly correlated with the degree of tumor budding and tCD15 in whole tissue sections was closely associated with tumor depth.

Conclusions

The present study suggests that the expression of CD10 and CD15 is associated with the development and progression of CRC.

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Review
Article image
Standardized Pathology Report for Colorectal Cancer, 2nd Edition
Baek-hui Kim, Joon Mee Kim, Gyeong Hoon Kang, Hee Jin Chang, Dong Wook Kang, Jung Ho Kim, Jeong Mo Bae, An Na Seo, Ho Sung Park, Yun Kyung Kang, Kyung-Hwa Lee, Mee Yon Cho, In-Gu Do, Hye Seung Lee, Hee Kyung Chang, Do Youn Park, Hyo Jeong Kang, Jin Hee Sohn, Mee Soo Chang, Eun Sun Jung, So-Young Jin, Eunsil Yu, Hye Seung Han, Youn Wha Kim
J Pathol Transl Med. 2020;54(1):1-19.   Published online November 13, 2019
DOI: https://doi.org/10.4132/jptm.2019.09.28
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AbstractAbstract PDFSupplementary Material
The first edition of the ‘Standardized Pathology Report for Colorectal Cancer,’ which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of “standard data elements” and “conditional data elements.” Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as “standard data elements,” while other prognostic factors and factors related to adjuvant therapy are classified as “conditional data elements” so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.

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Original Article
PD-L1 Expression and Combined Status of PD-L1/PD-1–Positive Tumor Infiltrating Mononuclear Cell Density Predict Prognosis in Glioblastoma Patients
Jiheun Han, Yongkil Hong, Youn Soo Lee
J Pathol Transl Med. 2017;51(1):40-48.   Published online December 15, 2016
DOI: https://doi.org/10.4132/jptm.2016.08.31
  • 16,227 View
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AbstractAbstract PDF
Background
Programmed death ligand 1 (PD-L1) in tumor cells is known to promote immune escape of cancer by interacting with programmed cell death 1 (PD-1) in tumor infiltrating immune cells. Immunotherapy targeting these molecules is emerging as a new strategy for the treatment of glioblastoma (GBM). Understanding the relationship between the PD-L1/PD-1 axis and prognosis in GBM patients may be helpful to predict the effects of immunotherapy.
Methods
PD-L1 expression and PD-1–positive tumor infiltrating mononuclear cell (PD-1+tumor infiltrating mononuclear cell [TIMC]) density were evaluated using tissue microarray containing 54 GBM cases by immunohistochemical analysis; the associations with patient clinical outcomes were evaluated.
Results
PD-L1 expression and high PD-1+TIMC density were observed in 31.5% and 50% of GBM cases, respectively. High expression of PD-L1 in tumor cells was an independent and significant predictive factor for worse overall survival (OS; hazard ratio, 4.958; p = .007) but was not a significant factor in disease-free survival (DFS). PD-1+TIMC density was not correlated with OS or DFS. When patients were classified based on PD-1 expression and PD-1+TIMC density, patients with PD-L1+/PD-1+TIMC low status had the shortest OS (13 months, p = .009) and DFS (7 months, p = .053).
Conclusions
PD-L1 expression in GBM was an independent prognostic factor for poor OS. In addition, combined status of PD-L1 expression and PD-1+TIMC density also predicted patient outcomes, suggesting that the therapeutic role of the PD-1/PD-L1 axis should be considered in the context of GBM immunity.

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Reviews
Good Laboratory Standards for Clinical Next-Generation Sequencing Cancer Panel Tests
Jihun Kim, Woong-Yang Park, Nayoung K. D. Kim, Se Jin Jang, Sung-Min Chun, Chang-Ohk Sung, Jene Choi, Young-Hyeh Ko, Yoon-La Choi, Hyo Sup Shim, Jae-Kyung Won
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DOI: https://doi.org/10.4132/jptm.2017.03.14
  • 28,756 View
  • 1,110 Download
  • 36 Web of Science
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AbstractAbstract PDF
Next-generation sequencing (NGS) has recently emerged as an essential component of personalized cancer medicine due to its high throughput and low per-base cost. However, no sufficient guidelines for implementing NGS as a clinical molecular pathology test are established in Korea. To ensure clinical grade quality without inhibiting adoption of NGS, a taskforce team assembled by the Korean Society of Pathologists developed laboratory guidelines for NGS cancer panel testing procedures and requirements for clinical implementation of NGS. This consensus standard proposal consists of two parts: laboratory guidelines and requirements for clinical NGS laboratories. The laboratory guidelines part addressed several important issues across multistep NGS cancer panel tests including choice of gene panel and platform, sample handling, nucleic acid management, sample identity tracking, library preparation, sequencing, analysis and reporting. Requirements for clinical NGS tests were summarized in terms of documentation, validation, quality management, and other required written policies. Together with appropriate pathologist training and international laboratory standards, these laboratory standards would help molecular pathology laboratories to successfully implement NGS cancer panel tests in clinic. In this way, the oncology community would be able to help patients to benefit more from personalized cancer medicine.

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Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer
Sung Gwe Ahn, Joon Jeong, SoonWon Hong, Woo Hee Jung
J Pathol Transl Med. 2015;49(5):355-363.   Published online August 17, 2015
DOI: https://doi.org/10.4132/jptm.2015.07.29
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AbstractAbstract PDF
With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

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Acute Atherosis of the Uterine Spiral Arteries: Clinicopathologic Implications
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J Pathol Transl Med. 2015;49(6):462-471.   Published online November 4, 2015
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  • 19,939 View
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  • 34 Web of Science
  • 36 Crossref
AbstractAbstract PDF
Acute atherosis is unique vascular changes of the placenta associated with poor placentation. It is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis of the arterial wall, perivascular lymphocytic infiltration, and it is histologically similar to early-stage atherosclerosis. Acute atherosis is rare in normal pregnancies, but is frequently observed in non- transformed spiral arteries in abnormal pregnancies, such as preeclampsia, small for gestational age (SGA), fetal death, spontaneous preterm labor and preterm premature rupture of membranes. In preeclampsia, spiral arteries fail to develop physiologic transformation and retain thick walls and a narrow lumen. Failure of physiologic transformation of spiral arteries is believed to be the main cause of uteroplacental ischemia, which can lead to the production of anti-angiogenic factors and induce endothelial dysfunction and eventually predispose the pregnancy to preeclampsia. Acute atherosis is more frequently observed in the spiral arteries of the decidua of the placenta (parietalis or basalis) than in the decidual or myometrial segments of the placental bed. The presence and deeper location of acute atherosis is associated with poorer pregnancy outcomes, more severe disease, earlier onset of preeclampsia, and a greater frequency of SGA neonates in patients with preeclampsia. Moreover, the idea that the presence of acute atherosis in the placenta may increase the risk of future cardiovascular disease in women with a history of preeclampsia is of growing concern. Therefore, placental examination is crucial for retrospective investigation of pregnancy complications and outcomes, and accurate placental pathology based on universal diagnostic criteria in patients with abnormal pregnancies is essential for clinicopathologic correlation.

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Current Concepts and Occurrence of Epithelial Odontogenic Tumors: II. Calcifying Epithelial Odontogenic Tumor Versus Ghost Cell Odontogenic Tumors Derived from Calcifying Odontogenic Cyst
Suk Keun Lee, Yeon Sook Kim
Korean J Pathol. 2014;48(3):175-187.   Published online June 26, 2014
DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.3.175
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AbstractAbstract PDF

Calcifying epithelial odontogenic tumors (CEOTs) and ghost cell odontogenic tumors (GCOTs) are characteristic odontogenic origin epithelial tumors which produce calcifying materials from transformed epithelial tumor cells. CEOT is a benign odontogenic tumor composed of polygonal epithelial tumor cells that show retrogressive calcific changes, amyloid-like deposition, and clear cytoplasm. Differentially, GCOTs are a group of transient tumors characterized by ghost cell presence, which comprise calcifying cystic odontogenic tumor (CCOT), dentinogenic ghost cell tumor (DGCT), and ghost cell odontogenic carcinoma (GCOC), all derived from calcifying odontogenic cysts (COCs). There is considerable confusion about COCs and GCOTs terminology, but these lesions can be classified as COCs or GCOTs, based on their cystic or tumorous natures, respectively. GCOTs include ameloblastomatous tumors derived from dominant odontogenic cysts classified as CCOTs, ghost cell-rich tumors producing dentinoid materials as DGCTs, and the GCOT malignant counterpart, GCOCs. Many authors have reported CEOTs and GCOTs variably express keratins, β-catenin, BCL-2, BSP, RANKL, OPG, Notch1, Jagged1, TGF-β, SMADs, and other proteins. However, these heterogeneous lesions should be differentially diagnosed to allow for accurate tumor progression and prognosis prediction.

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Original Articles
Article image
Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer
Hye Jung Hwang, Soo Kyung Nam, Hyunjin Park, Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Woo Ho Kim, Hye Seung Lee
J Pathol Transl Med. 2020;54(5):378-386.   Published online July 1, 2020
DOI: https://doi.org/10.4132/jptm.2020.06.01
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AbstractAbstract PDFSupplementary Material
Background
Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC.
Methods
Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated.
Results
Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035).
Conclusions
Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

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Alteration of the E-Cadherin/β-Catenin Complex Is an Independent Poor Prognostic Factor in Lung Adenocarcinoma
Hyojin Kim, Seol Bong Yoo, Pingli Sun, Yan Jin, Sanghoon Jheon, Choon Taek Lee, Jin-Haeng Chung
Korean J Pathol. 2013;47(1):44-51.   Published online February 25, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.44
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AbstractAbstract PDF
Background

Epithelial-mesenchymal transition (EMT) is an important step in the invasion and progression of cancer and in the development of chemoresistance by cancer cells.

Methods

To address the clinical significance of the EMT pathway in lung adenocarcinoma and the association of the pathway with histological subtype, we examined 193 surgically resected lung adenocarcinoma samples for the expression of representative EMT-related proteins (E-cadherin, β-catenin, and vimentin) by immunohistochemistry. Histological subtypes were classified according to the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The results for EMT-related protein expression were analyzed for correlation with clinicopathological features and with survival.

Results

The loss of E-cadherin expression and aberrant β-catenin expression were significantly associated with larger tumor size, pleural invasion, lymphatic/vascular invasion, and advanced pathological stage (p<0.05). The alteration of the E-cadherin/β-catenin complex was least frequently observed in the lepidic-predominant group, but these associations were not statistically significant. In the multivariate analysis, altered E-cadherin/β-catenin complex expression was found to be an independent poor prognostic factor (p=0.017; hazard ratio, 1.926; 95% confidence interval, 1.119 to 3.314).

Conclusions

The alteration of the expression of the E-cadherin/β-catenin complex was associated with aggressive tumor behavior in lung adenocarcinoma.

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Reviews
Article image
Perspectives on single-nucleus RNA sequencing in different cell types and tissues
Nayoung Kim, Huiram Kang, Areum Jo, Seung-Ah Yoo, Hae-Ock Lee
J Pathol Transl Med. 2023;57(1):52-59.   Published online January 10, 2023
DOI: https://doi.org/10.4132/jptm.2022.12.19
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AbstractAbstract PDF
Single-cell RNA sequencing has become a powerful and essential tool for delineating cellular diversity in normal tissues and alterations in disease states. For certain cell types and conditions, there are difficulties in isolating intact cells for transcriptome profiling due to their fragility, large size, tight interconnections, and other factors. Single-nucleus RNA sequencing (snRNA-seq) is an alternative or complementary approach for cells that are difficult to isolate. In this review, we will provide an overview of the experimental and analysis steps of snRNA-seq to understand the methods and characteristics of general and tissue-specific snRNA-seq data. Knowing the advantages and limitations of snRNA-seq will increase its use and improve the biological interpretation of the data generated using this technique.

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Article image
Inflammatory bowel disease–associated intestinal fibrosis
Ji Min Park, Jeongseok Kim, Yoo Jin Lee, Sung Uk Bae, Hye Won Lee
J Pathol Transl Med. 2023;57(1):60-66.   Published online January 10, 2023
DOI: https://doi.org/10.4132/jptm.2022.11.02
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AbstractAbstract PDF
Fibrosis is characterized by a proliferation of fibroblasts and excessive extracellular matrix following chronic inflammation, and this replacement of organ tissue with fibrotic tissue causes a loss of function. Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract, and intestinal fibrosis is common in IBD patients, resulting in several complications that require surgery, such as a stricture or penetration. This review describes the pathogenesis and various factors involved in intestinal fibrosis in IBD, including cytokines, growth factors, epithelial-mesenchymal and endothelial-mesenchymal transitions, and gut microbiota. Furthermore, histopathologic findings and scoring systems used for stenosis in IBD are discussed, and differences in the fibrosis patterns of ulcerative colitis and Crohn’s disease are compared. Biomarkers and therapeutic agents targeting intestinal fibrosis are briefly mentioned at the end.

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Original Articles
Article image
The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis
Alaa Salah Jumaah, Mais Muhammed Salim, Hawraa Sahib Al-Haddad, Katherine Ann McAllister, Akeel Abed Yasseen
J Pathol Transl Med. 2020;54(6):471-479.   Published online September 2, 2020
DOI: https://doi.org/10.4132/jptm.2020.07.23
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AbstractAbstract PDFSupplementary Material
Background
Endometrial carcinoma (EC) is classified into four distinct molecular subgroups including ultramutated DNA polymerase epsilon (POLE). POLE-mutated tumors have the best prognosis and are a promising target for immunotherapy. This meta-analysis consolidated the reported variation of POLE-mutant frequency and assessed prognostic value in EC.
Methods
Internet searches explored scientific data bases: EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials databases. Data was extracted from eligible studies including: sample size, number of positive POLE-mutant cases, sequencing information, clinicopathologic data, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE frequency and prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odd ratios (OR).
Results
Six thousand three hundred and forty-six EC patient cases were pooled from 25 studies. The pooled proportion of POLE gene mutation in EC was 8.59% (95% CI, 7.01 to 10.32), of which 8.22% (95% CI, 6.27 to 10.42) were type I and 0.93% (95% CI, 0.34 to 1.81) type 2. Clinicopathologic data showed that POLE-mutated tumors are mostly endometrioid. They present at higher levels in earlier stages (I–II) of EC (89.51%; 95% CI, 81.11 to 95.66) at the highest grade III (51.53%; 95% CI, 36.08 to 66.84) with reduced myometrial invasion (OR, 1.48, 95% CI, 0.99 to 2.20). Survival analysis indicated favorable overall survival (HR, 0.90), disease-specific survival (HR, 0.41), and progression-free survival (HR, 0.23) for POLE mutant EC.
Conclusions
Almost one-tenth of EC patients have POLE-mutated tumors. Given their improved prognostic potential, identifying the POLE mutation status is key for the management of EC patients.

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Article image
Interobserver Reproducibility of PD-L1 Biomarker in Non-small Cell Lung Cancer: A Multi-Institutional Study by 27 Pathologists
Sunhee Chang, Hyung Kyu Park, Yoon-La Choi, Se Jin Jang
J Pathol Transl Med. 2019;53(6):347-353.   Published online October 28, 2019
DOI: https://doi.org/10.4132/jptm.2019.09.29
  • 8,098 View
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  • 36 Web of Science
  • 34 Crossref
AbstractAbstract PDF
Background
Assessment of programmed cell death-ligand 1 (PD-L1) immunohistochemical staining is used for treatment decisions in non-small cell lung cancer (NSCLC) regarding use of PD-L1/programmed cell death protein 1 (PD-1) immunotherapy. The reliability of the PD-L1 22C3 pharmDx assay is critical in guiding clinical practice. The Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists investigated the interobserver reproducibility of PD-L1 staining with 22C3 pharmDx in NSCLC samples.
Methods
Twenty-seven pathologists individually assessed the tumor proportion score (TPS) for 107 NSCLC samples. Each case was divided into three levels based on TPS: <1%, 1%–49%, and ≥50%.
Results
The intraclass correlation coefficient for TPS was 0.902±0.058. Weighted κ coefficient for 3-step assessment was 0.748±0.093. The κ coefficients for 1% and 50% cut-offs were 0.633 and 0.834, respectively. There was a significant association between interobserver reproducibility and experience (formal PD-L1 training, more experience for PD-L1 assessment, and longer practice duration on surgical pathology), histologic subtype, and specimen type.
Conclusions
Our results indicate that PD-L1 immunohistochemical staining provides a reproducible basis for decisions on anti–PD-1 therapy in NSCLC.

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Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer
Hong Sik Park, Uiju Cho, So Young Im, Chang Young Yoo, Ji Han Jung, Young Jin Suh, Hyun Joo Choi
J Pathol Transl Med. 2019;53(2):75-85.   Published online November 14, 2018
DOI: https://doi.org/10.4132/jptm.2018.10.11
  • 8,994 View
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  • 33 Web of Science
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AbstractAbstract PDF
Background
Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear.
Methods
We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed.
Results
Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II–IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I–positive tumors than in HLA-I–negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort.
Conclusions
Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.

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Review
The Utilization of Cytologic Fine-Needle Aspirates of Lung Cancer for Molecular Diagnostic Testing
Michael H. Roh
J Pathol Transl Med. 2015;49(4):300-309.   Published online June 16, 2015
DOI: https://doi.org/10.4132/jptm.2015.06.16
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AbstractAbstract PDF
In this era of precision medicine, our understanding and knowledge of the molecular landscape associated with lung cancer pathogenesis continues to evolve. This information is being increasingly exploited to treat advanced stage lung cancer patients with tailored, targeted therapy. During the management of these patients, minimally invasive procedures to obtain samples for tissue diagnoses are desirable. Cytologic fine-needle aspirates are often utilized for this purpose and are important not only for rendering diagnoses to subtype patients’ lung cancers, but also for ascertaining molecular diagnostic information for treatment purposes. Thus, cytologic fine-needle aspirates must be utilized and triaged judiciously to achieve both objectives. In this review, strategies in utilizing fine-needle aspirates will be discussed in the context of our current understanding of the clinically actionable molecular aberrations underlying non-small cell lung cancer and the molecular assays applied to these samples in order to obtain treatment-relevant molecular diagnostic information.

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