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Original Article
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Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing
Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung
J Pathol Transl Med. 2022;56(5):249-259.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.06.11
  • 2,913 View
  • 118 Download
  • 2 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary Material
Background
Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are predictive biomarkers for response to EGFR–tyrosine kinase inhibitor (TKI) therapy in lung adenocarcinoma (LUAD). Here, we characterized the clinicopathologic features associated with EGFR mutations via peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper) and evaluated the feasibility of targeted deep sequencing for detecting the mutations.
Methods
We examined EGFR mutations in exons 18 through 21 for 2,088 LUADs from July 2017 to April 2020 using PANAMutyper. Of these, we performed targeted deep sequencing in 73 patients and evaluated EGFR-mutation status and TKI clinical response.
Results
EGFR mutation was identified in 55.7% of LUADs by PANAMutyper, with mutation rates higher in females (69.3%) and never smokers (67.1%) and highest in the age range of 50 to 59 years (64.9%). For the 73 patients evaluated using both methods, next-generation sequencing (NGS) identified EGFR mutation–positive results in 14 of 61 patients (23.0%) who were EGFR-negative according to PANAMutyper testing. Of the 10 patients reportedly harboring a sensitizing mutation according to NGS, seven received TKI treatment, with all showing partial response or stable disease. In the 12 PANAMutyper-positive cases, NGS identified two additional mutations in exon 18, whereas a discordant negative result was observed in two cases.
Conclusions
Although PANAMutyper identified high frequencies of EGFR mutations, targeted deep sequencing revealed additional uncommon EGFR mutations. These findings suggested that appropriate use of NGS may benefit LUAD patients with otherwise negative screening test results.

Citations

Citations to this article as recorded by  
  • Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine
    Jieun Park, Boram Lee, Ji-Young Song, Minjung Sung, Mi Jeong Kwon, Chae Rin Kim, Sangjin Lee, Young Kee Shin, Yoon-La Choi
    Pathology.2024; 56(5): 653.     CrossRef
  • Histo-pillar strip for optimal histogel block construction and biomarker analysis in 3D-lung cancer patient-derived organoids
    Sang-Yun Lee, Eunyoung Lee, Ji-O Ryu, Kyuhwan Kim, Yongki Hwang, Bosung Ku, Seok Whan Moon, Mi Hyoung Moon, Kyung Soo Kim, Kwanyong Hyun, Jeong Uk Lim, Chan Kwon Park, Sung Won Kim, Chang Dong Yeo, Dong Woo Lee, Seung Joon Kim
    Biofabrication.2024; 16(4): 045017.     CrossRef
Case Study
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A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma
Ki-Chang Lee, Jiwon Koh, Doo Hyun Chung, Yoon Kyung Jeon
J Pathol Transl Med. 2021;55(2):139-144.   Published online January 22, 2021
DOI: https://doi.org/10.4132/jptm.2020.12.16
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  • 4 Web of Science
  • 3 Crossref
AbstractAbstract PDF
Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

Citations

Citations to this article as recorded by  
  • Identification and validation of molecular subtype and prognostic signature for lung adenocarcinoma based on neutrophil extracellular traps
    Yanhua Zuo, Guangyi Leng, Ping Leng
    Pathology and Oncology Research.2023;[Epub]     CrossRef
  • Machine Learning-Based Integration Develops a Macrophage-Related Index for Predicting Prognosis and Immunotherapy Response in Lung Adenocarcinoma
    Zuwei Li, Minzhang Guo, Wanli Lin, Peiyuan Huang
    Archives of Medical Research.2023; 54(7): 102897.     CrossRef
  • Big data analysis identified a telomere-related signature predicting the prognosis and drug sensitivity in lung adenocarcinoma
    Weiyi Zhang
    Medicine.2023; 102(46): e35526.     CrossRef
Review
Article image
Current status and future perspectives of liquid biopsy in non-small cell lung cancer
Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim
J Pathol Transl Med. 2020;54(3):204-212.   Published online April 15, 2020
DOI: https://doi.org/10.4132/jptm.2020.02.27
  • 7,912 View
  • 284 Download
  • 17 Web of Science
  • 16 Crossref
AbstractAbstract PDF
With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

Citations

Citations to this article as recorded by  
  • Unlocking the future of cancer diagnosis – promises and challenges of ctDNA-based liquid biopsies in non-small cell lung cancer
    Chiara Reina, Berina Šabanović, Chiara Lazzari, Vanesa Gregorc, Christopher Heeschen
    Translational Research.2024; 272: 41.     CrossRef
  • Tailored point-of-care biosensors for liquid biopsy in the field of oncology
    Sima Singh, Pritam Saha Podder, Matt Russo, Charles Henry, Stefano Cinti
    Lab on a Chip.2023; 23(1): 44.     CrossRef
  • Emerging role of non-invasive and liquid biopsy biomarkers in pancreatic cancer
    Akash Bararia, Prosenjeet Chakraborty, Paromita Roy, Bitan Kumar Chattopadhay, Amlan Das, Aniruddha Chatterjee, Nilabja Sikdar
    World Journal of Gastroenterology.2023; 29(15): 2241.     CrossRef
  • Liquid biopsy in the management of advanced lung cancer: Implementation and practical aspects
    Gabriela Fernandes, Ana Rodrigues, Cláudia Matos, Fernando Barata, Luís Cirnes, Lurdes Ferreira, José Albino Lopes, Margarida Felizardo, Paula Fidalgo, Ulisses Brito, Bárbara Parente
    Cancer Treatment and Research Communications.2023; 36: 100725.     CrossRef
  • Tweezer PCR: A Highly Specific Method for Accurate Identification of Low-Abundance Mutations
    Shanglin Li, Yin Gu, Zhi Geng, Kaiyi Li, Yawei Hu, Qiang Liu, Rongxin Fu, Peng Liu
    Analytical Chemistry.2023; 95(48): 17679.     CrossRef
  • Mesonephric-like Adenocarcinoma of the Ovary: Clinicopathological and Molecular Characteristics
    Hyun Hee Koh, Eunhyang Park, Hyun-Soo Kim
    Diagnostics.2022; 12(2): 326.     CrossRef
  • Alveolar Soft Part Sarcoma of the Uterus: Clinicopathological and Molecular Characteristics
    Yurimi Lee, Kiyong Na, Ha Young Woo, Hyun-Soo Kim
    Diagnostics.2022; 12(5): 1102.     CrossRef
  • Exosomal MicroRNA Analyses in Esophageal Squamous Cell Carcinoma Cell Lines
    Sora Kim, Gwang Ha Kim, Su Jin Park, Chae Hwa Kwon, Hoseok I, Moon Won Lee, Bong Eun Lee
    Journal of Clinical Medicine.2022; 11(15): 4426.     CrossRef
  • Molecular biomarker testing for non–small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group
    Sunhee Chang, Hyo Sup Shim, Tae Jung Kim, Yoon-La Choi, Wan Seop Kim, Dong Hoon Shin, Lucia Kim, Heae Surng Park, Geon Kook Lee, Chang Hun Lee
    Journal of Pathology and Translational Medicine.2021; 55(3): 181.     CrossRef
  • Update on molecular pathology and role of liquid biopsy in nonsmall cell lung cancer
    Pamela Abdayem, David Planchard
    European Respiratory Review.2021; 30(161): 200294.     CrossRef
  • Dynamics of Specific cfDNA Fragments in the Plasma of Full Marathon Participants
    Takehito Sugasawa, Shin-ichiro Fujita, Tomoaki Kuji, Noriyo Ishibashi, Kenshirou Tamai, Yasushi Kawakami, Kazuhiro Takekoshi
    Genes.2021; 12(5): 676.     CrossRef
  • Future Perspectives in Detecting EGFR and ALK Gene Alterations in Liquid Biopsies of Patients with NSCLC
    Daniela Ferreira, Juliana Miranda, Paula Martins-Lopes, Filomena Adega, Raquel Chaves
    International Journal of Molecular Sciences.2021; 22(8): 3815.     CrossRef
  • Real-World Analysis of the EGFR Mutation Test in Tissue and Plasma Samples from Non-Small Cell Lung Cancer
    Hyunwoo Lee, Joungho Han, Yoon-La Choi
    Diagnostics.2021; 11(9): 1695.     CrossRef
  • Objective Quantitation of EGFR Protein Levels using Quantitative Dot Blot Method for the Prognosis of Gastric Cancer Patients
    Lei Xin, Fangrong Tang, Bo Song, Maozhou Yang, Jiandi Zhang
    Journal of Gastric Cancer.2021; 21(4): 335.     CrossRef
  • The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer
    D. Akhoundova, J. Mosquera Martinez, L. E. Musmann, C. Britschgi, C. Rütsche, M. Rechsteiner, E. Nadal, M. R. Garcia Campelo, A. Curioni-Fontecedro
    Journal of Clinical Medicine.2020; 9(11): 3674.     CrossRef
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    T Raja
    Cancer Research, Statistics, and Treatment.2020; 3(4): 863.     CrossRef
Original Article
Article image
Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer
Ye Sul Jeong, Jun Kang, Jieun Lee, Tae-Kyung Yoo, Sung Hun Kim, Ahwon Lee
J Pathol Transl Med. 2020;54(1):87-94.   Published online November 13, 2019
DOI: https://doi.org/10.4132/jptm.2019.10.14
  • 6,735 View
  • 203 Download
  • 15 Web of Science
  • 17 Crossref
AbstractAbstract PDF
Background
Accurate molecular classification of breast core needle biopsy (CNB) tissue is important for determining neoadjuvant systemic therapies for invasive breast cancer. The researchers aimed to evaluate the concordance rate (CR) of molecular subtypes between CNBs and surgical specimens.
Methods
This study was conducted with invasive breast cancer patients who underwent surgery after CNB at Seoul St. Mary’s Hospital between December 2014 and December 2017. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 were analyzed using immunohistochemistry. ER and PR were evaluated by Allred score (0–8). HER2 was graded from 0 to +3, and all 2+ cases were reflex tested with silver in situ hybridization. The labeling index of Ki67 was counted by either manual scoring or digital image analysis. Molecular subtypes were classified using the above surrogate markers.
Results
In total, 629 patients were evaluated. The CRs of ER, PR, HER2, and Ki67 were 96.5% (kappa, 0.883; p<.001), 93.0% (kappa, 0.824; p<.001), 99.7% (kappa, 0.988; p<.001), and 78.7% (kappa, 0.577; p<.001), respectively. Digital image analysis of Ki67 in CNB showed better concordance with Ki67 in surgical specimens (CR, 82.3%; kappa, 0.639 for digital image analysis vs. CR, 76.2%; kappa, 0.534 for manual counting). The CRs of luminal A, luminal B, HER2, and triple negative types were 89.0%, 70.0%, 82.9%, and 77.2%, respectively.
Conclusions
CNB was reasonably accurate for determining ER, PR, HER2, Ki67, and molecular subtypes. Using digital image analysis for Ki67 in CNB produced more accurate molecular classifications.

Citations

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  • Impact of immunohistochemistry staining conditions on the incidence of human epidermal growth factor receptor 2 (HER2)-low breast cancer
    Min Chong Kim, Sun Young Kwon, Hye Ra Jung, Young Kyung Bae
    Virchows Archiv.2024;[Epub]     CrossRef
  • Study on Intratumoral Heterogeneity of Expression of Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 in Carcinoma Breast
    Ragavi Uthayasuriyan, Sheba K Jacob, Saloni Naresh Shah
    Apollo Medicine.2024; 21(1): 51.     CrossRef
  • Concordance of HER2 status between core needle biopsy and surgical resection specimens of breast cancer: an analysis focusing on the HER2-low status
    Sei Na, Milim Kim, Yujun Park, Hyun Jung Kwon, Hee-Chul Shin, Eun-Kyu Kim, Mijung Jang, Sun Mi Kim, So Yeon Park
    Breast Cancer.2024; 31(4): 705.     CrossRef
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Case Study
Article image
Morule-like features in pulmonary adenocarcinoma associated with epidermal growth factor receptor mutations: two case reports with targeted next-generation sequencing analysis
Yoo Jin Lee, Harim Oh, Eojin Kim, Bokyung Ahn, Jeong Hyeon Lee, Youngseok Lee, Yang Seok Chae, Chul Hwan Kim
J Pathol Transl Med. 2020;54(1):119-122.   Published online November 1, 2019
DOI: https://doi.org/10.4132/jptm.2019.09.30
  • 4,721 View
  • 128 Download
  • 2 Web of Science
  • 2 Crossref
AbstractAbstract PDF
Morules, or morule-like features, can be identified in benign and malignant lesions in various organs. Morular features are unusual in pulmonary adenocarcinoma cases with only 26 cases reported to date. Here, we describe two cases of pulmonary adenocarcinoma with morule-like features in Korean women. One patient had a non-mucinous-type adenocarcinoma in situ and the other had an acinarpredominant adenocarcinoma with a micropapillary component. Both patients showed multiple intra-alveolar, nodular, whorled proliferative foci composed of atypical spindle cells with eosinophilic cytoplasm. Targeted next-generation sequencing was performed on DNA extracted from formalin-fixed paraffin-embedded samples of the tumors. Results showed unusual epidermal growth factor receptor (EGFR) mutations, which are associated with drug resistance to EGFR tyrosine kinase inhibitors, revealing the importance of identifying morule-like features in pulmonary adenocarcinoma and the need for additional study, since there are few reported cases.

Citations

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  • Pulmonary adenocarcinoma in situ with morule - like components: A surgical case report
    Mitsuteru Yosida, Mitsuru Tomita, Naoya Kawakita, Teruki Shimizu, Ryou Yamada, Hiromitsu Takizawa, Hisanori Uehara
    Respiratory Medicine Case Reports.2024; 48: 102008.     CrossRef
  • Clinicopathological, Radiological, and Molecular Features of Primary Lung Adenocarcinoma with Morule-Like Components
    Li-Li Wang, Li Ding, Peng Zhao, Jing-Jing Guan, Xiao-Bin Ji, Xiao-Li Zhou, Shi-Hong Shao, Yu-Wei Zou, Wei-Wei Fu, Dong-Liang Lin, Dong Pan
    Disease Markers.2021; 2021: 1.     CrossRef
Review
Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group
Dong Hoon Shin, Hyo Sup Shim, Tae Jung Kim, Heae Surng Park, Yun La Choi, Wan Seop Kim, Lucia Kim, Sun Hee Chang, Joon Seon Song, Hyo jin Kim, Jung Ho Han, Chang Hun Lee, Geon Kook Lee, Se Jin Jang
J Pathol Transl Med. 2019;53(3):153-158.   Published online February 28, 2019
DOI: https://doi.org/10.4132/jptm.2019.02.22
  • 7,721 View
  • 255 Download
  • 6 Web of Science
  • 6 Crossref
AbstractAbstract PDF
Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50–60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

Citations

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    Chiara Reina, Berina Šabanović, Chiara Lazzari, Vanesa Gregorc, Christopher Heeschen
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    Sunhee Chang, Hyo Sup Shim, Tae Jung Kim, Yoon-La Choi, Wan Seop Kim, Dong Hoon Shin, Lucia Kim, Heae Surng Park, Geon Kook Lee, Chang Hun Lee
    Journal of Pathology and Translational Medicine.2021; 55(3): 181.     CrossRef
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    Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim
    Journal of Pathology and Translational Medicine.2020; 54(3): 204.     CrossRef
  • Prevalence of T790M mutation among TKI-therapy resistant Lebanese lung cancer patients based on liquid biopsy analysis: a first report from a major tertiary care center
    Hazem Assi, Arafat Tfayli, Nada Assaf, Sarah Abou Daya, Aram H. Bidikian, Dima Kawsarani, Puzant Fermanian, Ghazi Zaatari, Rami Mahfouz
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Original Articles
Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01)
Bo Mi Ku, Mi Hwa Heo, Joo-Hang Kim, Byoung Chul Cho, Eun Kyung Cho, Young Joo Min, Ki Hyeong Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Tae Jung Kim, Ho Yun Lee, Hojoong Kim, Kyung-Jong Lee, Myung-Ju Ahn
J Pathol Transl Med. 2018;52(3):148-156.   Published online March 26, 2018
DOI: https://doi.org/10.4132/jptm.2018.03.12
  • 7,812 View
  • 301 Download
  • 16 Web of Science
  • 13 Crossref
AbstractAbstract PDF
Background
Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC.
Methods
DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Results
The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study.
Conclusions
These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

Citations

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    Glena Travis, Eileen M. McGowan, Ann M. Simpson, Deborah J. Marsh, Najah T. Nassif
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  • Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing
    Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung
    Journal of Pathology and Translational Medicine.2022; 56(5): 249.     CrossRef
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    Journal of Pathology and Translational Medicine.2021; 55(3): 181.     CrossRef
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    Hengrui Liang, Caichen Li, Yi Zhao, Shen Zhao, Jun Huang, Xiuyu Cai, Bo Cheng, Shan Xiong, Jianfu Li, Wei Wang, Changbin Zhu, Weiwei Li, Jianxing He, Wenhua Liang
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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
  • 11,177 View
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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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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
  • 18,047 View
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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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Analysis of Mutations in Epidermal Growth Factor Receptor Gene in Korean Patients with Non-small Cell Lung Cancer: Summary of a Nationwide Survey
Sang Hwa Lee, Wan Seop Kim, Yoo Duk Choi, Jeong Wook Seo, Joung Ho Han, Mi Jin Kim, Lucia Kim, Geon Kook Lee, Chang Hun Lee, Mee Hye Oh, Gou Young Kim, Sun Hee Sung, Kyo Young Lee, Sun Hee Chang, Mee Sook Rho, Han Kyeom Kim, Soon Hee Jung, Se Jin Jang, The Cardiopulmonary Pathology Study Group of Korean Society of Pathologists
J Pathol Transl Med. 2015;49(6):481-488.   Published online October 13, 2015
DOI: https://doi.org/10.4132/jptm.2015.09.14
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  • 19 Web of Science
  • 21 Crossref
AbstractAbstract PDF
Background
Analysis of mutations in the epidermal growth factor receptor gene (EGFR) is important for predicting response to EGFR tyrosine kinase inhibitors. The overall rate of EGFR mutations in Korean patients is variable. To obtain comprehensive data on the status of EGFR mutations in Korean patients with lung cancer, the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists initiated a nationwide survey. Methods: We obtained 1,753 reports on EGFR mutations in patients with lung cancer from 15 hospitals between January and December 2009. We compared EGFR mutations with patient age, sex, history of smoking, histologic diagnosis, specimen type, procurement site, tumor cell dissection, and laboratory status. Results: The overall EGFR mutation rate was 34.3% in patients with non-small cell lung cancer (NSCLC) and 43.3% in patients with adenocarcinoma. EGFR mutation rate was significantly higher in women, never smokers, patients with adenocarcinoma, and patients who had undergone excisional biopsy. EGFR mutation rates did not differ with respect to patient age or procurement site among patients with NSCLC. Conclusions: EGFR mutation rates and statuses were similar to those in published data from other East Asian countries.

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Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma
Eunhyang Park, Soo Young Park, Hyojin Kim, Ping-Li Sun, Yan Jin, Suk Ki Cho, Kwhanmien Kim, Choon-Taek Lee, Jin-Haeng Chung
J Pathol Transl Med. 2015;49(5):382-388.   Published online August 4, 2015
DOI: https://doi.org/10.4132/jptm.2015.07.10
  • 8,120 View
  • 100 Download
  • 22 Web of Science
  • 17 Crossref
AbstractAbstract PDF
Background
Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. Methods: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. Results: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). Conclusions: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.

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    Tu-Chen Liu, Ming-Ju Hsieh, Ming-Che Liu, Whei-Ling Chiang, Thomas Tsao, Shun-Fa Yang
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EGFR Gene Amplification and Protein Expression in Invasive Ductal Carcinoma of the Breast
Won Hwangbo, Jeong Hyeon Lee, Sangjeong Ahn, Seojin Kim, Kyong Hwa Park, Chul Hwan Kim, Insun Kim
Korean J Pathol. 2013;47(2):107-115.   Published online April 24, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.107
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AbstractAbstract PDF
Background

The epidermal growth factor receptor (EGFR) is a surrogate marker for basal-like breast cancer. A recent study suggested that EGFR may be used as a target for breast cancer treatment.

Methods

A total of 706 invasive ductal carcinomas (IDC) of the breast were immunophenotyped, and 82 cases with EGFR protein expression were studied for EGFR gene amplification.

Results

EGFR protein was expressed in 121 of 706 IDCs (17.1%); 5.9% were of luminal type, 25.3% of epidermal growth factor receptor 2 (HER-2) type, and 79.3% of basal-like tumors. EGFR gene amplification and high polysomy (fluorescent in situ hybridization [FISH]-positive) were found in 18 of 82 cases (22.0%); 41.2% of the HER-2+, EGFR+, cytokeratin 5/6- (CK5/6-) group, 11.2% of the HER-2-, EGFR+, CK5/6- group, and 19.1% of the HER-2-, EGFR+, CK5/6+ group. FISH-positive cases were detected in 8.3% of the EGFR protein 1+ expression cases, 15.9% of 2+ expression cases, and 38.5% of 3+ expression cases. In group 2, the tumors had a high Ki-67 labeling (>60%), but the patients showed better disease-free survival than those with tumors that co-expressed HER-2 or CK5/6.

Conclusions

EGFR-directed therapy can be considered in breast cancer patients with EGFR protein overexpression and gene amplification, and its therapeutic implication should be determined in HER-2 type breast cancer patients.

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Review & Perspective
Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group
Hyo Sup Shim, Jin-Haeng Chung, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Geon Kook Lee, Soon-Hee Jung, Se Jin Jang
Korean J Pathol. 2013;47(2):100-106.   Published online April 24, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.100
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AbstractAbstract PDF

Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

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Original Articles
Comparison of Direct Sequencing, PNA Clamping-Real Time Polymerase Chain Reaction, and Pyrosequencing Methods for the Detection of EGFR Mutations in Non-small Cell Lung Carcinoma and the Correlation with Clinical Responses to EGFR Tyrosin
Hyun Ju Lee, Xianhua Xu, Hyojin Kim, Yan Jin, Pingli Sun, Ji Eun Kim, Jin-Haeng Chung
Korean J Pathol. 2013;47(1):52-60.   Published online February 25, 2013
DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.52
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AbstractAbstract PDF
Background

The aims of this study were to evaluate the abilities of direct sequencing (DS), peptide nucleic acid (PNA) clamping, and pyrosequencing methods to detect epidermal growth factor receptor (EGFR) mutations in formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) samples and to correlate EGFR mutational status as determined by each method with the clinical response to EGFR tyrosine kinase inhibitors (TKIs).

Methods

Sixty-one NSCLC patients treated with EGFR TKIs were identified to investigate somatic mutations in the EGFR gene (exons 18-21).

Results

Mutations in the EGFR gene were detected in 38 of the 61 patients (62%) by DS, 35 (57%) by PNA clamping and 37 (61%) by pyrosequencing. A total of 44 mutations (72%) were found by at least one of the three methods, and the concordances among the results were relatively high (82-85%; kappa coefficient, 0.713 to 0.736). There were 15 discordant cases (25%) among the three different methods.

Conclusions

All three EGFR mutation tests had good concordance rates (over 82%) for FFPE samples. These results suggest that if the DNA quality and enrichment of tumor cells are assured, then DS, PNA clamping, and pyrosequencing are appropriate methods for the detection of EGFR mutations.

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Intron 1 Polymorphism, Mutation and the Protein Expression of Epidermal Growth Factor Receptor in Relation to the Gefitinib Sensitivity of Korean Lung Cancer Patients.
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DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.6.509
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AbstractAbstract PDF
BACKGROUND
Epidermal growth factor receptor (EGFR) intron 1 polymorphism in non-small cell lung cancer (NSCLC) has been found to have therapeutic implications for the patients treated with EGFR tyrosine kinase inhibitors. However, its clinical significance as related to gefitinib responsiveness is still controversial. We examined CA repeat polymorphism in intron 1 of the EGFR gene and its relation with the EGFR gene mutation in NSCLC patients who were treated with gefitinib. METHODS: Sixty seven patients who were treated with gefitinib were analyzed for intron 1 polymorphism in the EGFR gene, the EGFR mutations and the EGFR protein expression. Two hundred twenty seven samples of NSCLC were analyzed for EGFR mutations. RESULTS: CA repeat was low in 27 patients (40.3%) and high in 40 (59.7%) patients. The response rate for gefitinib therapy was higher in the patient population with a low number of CA repeats in the EGFR gene (p=0.047) and in the patients with the mutated type of EGFR (p=0.048), though these two factors were not related. Thirty four patients (15.0%) harbored EGFR mutations. CONCLUSIONS: This study suggests that the intron 1 CA repeat polymorphism of the EGFR gene may serve as a predictor of the clinical outcome of NSCLC patients treated with gefitinib, and this without regard for EGFR mutation. Our data further supports the importance of EGFR mutations with regard to a distinct clinical profile and the prognostic implications for NSCLC patients.

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