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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
  • 2,912 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
  • 3,092 View
  • 103 Download
  • 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
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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
  • 7,911 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

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    Chiara Reina, Berina Šabanović, Chiara Lazzari, Vanesa Gregorc, Christopher Heeschen
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  • 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
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    Hyun Hee Koh, Eunhyang Park, Hyun-Soo Kim
    Diagnostics.2022; 12(2): 326.     CrossRef
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    Yurimi Lee, Kiyong Na, Ha Young Woo, Hyun-Soo Kim
    Diagnostics.2022; 12(5): 1102.     CrossRef
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    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
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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
  • 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 Articles
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Clinicopathologic characteristics of HER2-positive pure mucinous carcinoma of the breast
Yunjeong Jang, Hera Jung, Han-Na Kim, Youjeong Seo, Emad Alsharif, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Yeon Hee Park, Eun Yoon Cho, Soo Youn Cho
J Pathol Transl Med. 2020;54(1):95-102.   Published online November 13, 2019
DOI: https://doi.org/10.4132/jptm.2019.10.24
  • 7,583 View
  • 274 Download
  • 19 Web of Science
  • 18 Crossref
AbstractAbstract PDF
Background
Pure mucinous carcinoma (PMC) is a rare type of breast cancer, estimated to represent 2% of invasive breast cancer. PMC is typically positive for estrogen receptors (ER) and progesterone receptors (PR) and negative for human epidermal growth factor receptor 2 (HER2). The clinicopathologic characteristics of HER2-positive PMC have not been investigated.
Methods
Pathology archives were searched for PMC diagnosed from January 1999 to April 2018. Clinicopathologic data and microscopic findings were reviewed and compared between HER2-positive PMC and HER2-negative PMC. We also analyzed the differences in disease-free survival (DFS) and overall survival according to clinicopathologic parameters including HER2 status in overall PMC cases.
Results
There were 21 HER2-positive cases (4.8%) in 438 PMCs. The average tumor size of HER2-positive PMC was 32.21 mm (± 26.55). Lymph node metastasis was present in seven cases. Compared to HER2-negative PMC, HER2-positive PMC presented with a more advanced T category (p < .001), more frequent lymph node metastasis (p = .009), and a higher nuclear and histologic grade (p < .001). Microscopically, signet ring cells were frequently observed in HER2-positive PMC (p < .001), whereas a micropapillary pattern was more frequent in HER2-negative PMC (p = .012). HER2-positive PMC was more frequently negative for ER (33.3% vs. 1.2%) and PR (28.6% vs. 7.2%) than HER2-negative PMC and showed a high Ki-67 labeling index. During follow-up, distant metastasis and recurrence developed in three HER2-positive PMC patients. Multivariate analysis revealed that only HER2-positivity and lymph node status were significantly associated with DFS.
Conclusions
Our results suggest that HER2-positive PMC is a more aggressive subgroup of PMC. HER2 positivity should be considered for adequate management of PMC.

Citations

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    Breast Cancer Research and Treatment.2024;[Epub]     CrossRef
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    Journal of Breast Imaging.2023;[Epub]     CrossRef
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    RadioGraphics.2023;[Epub]     CrossRef
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    Hyun Hee Koh, Eunhyang Park, Hyun-Soo Kim
    Diagnostics.2022; 12(2): 326.     CrossRef
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    Yurimi Lee, Kiyong Na, Ha Young Woo, Hyun-Soo Kim
    Diagnostics.2022; 12(5): 1102.     CrossRef
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    Medicine.2022; 101(38): e30732.     CrossRef
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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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    Tiemo S. Gerber, Benjamin Goeppert, Anne Hausen, Hagen R. Witzel, Fabian Bartsch, Mario Schindeldecker, Lisa-Katharina Gröger, Dirk A. Ridder, Oscar Cahyadi, Irene Esposito, Matthias M. Gaida, Peter Schirmacher, Peter R. Galle, Hauke Lang, Wilfried Roth,
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Article image
Expression of female sex hormone receptors and its relation to clinicopathological characteristics and prognosis of lung adenocarcinoma
Jin Hwan Lee, Han Kyeom Kim, Bong Kyung Shin
J Pathol Transl Med. 2020;54(1):103-111.   Published online November 13, 2019
DOI: https://doi.org/10.4132/jptm.2019.10.12
  • 5,638 View
  • 138 Download
  • 5 Web of Science
  • 5 Crossref
AbstractAbstract PDF
Background
Adenocarcinoma (ADC) of the lung exhibits different clinicopathological characteristics in men and women. Recent studies have suggested that these differences originate from the expression of female sex hormone receptors in tumor cells. The aim of the present study was to evaluate the immunohistochemical expression of female sex hormone receptors in lung ADC and determine the expression patterns in patients with different clinicopathological characteristics.
Methods
A total of 84 patients with lung ADC who underwent surgical resection and/or core biopsy were recruited for the present study. Immunohistochemical staining was performed for estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR), epidermal growth factor receptor (EGFR), EGFR E746- A750 del, and EGFR L858R using tissue microarray.
Results
A total of 39 (46.4%) ERα-positive, 71 (84.5%) ERβ-positive, and 46 (54.8%) PR-positive lung ADCs were identified. In addition, there were 81 (96.4%) EGFR-positive, 14 (16.7%) EGFR E746-A750 del–positive, and 34 (40.5%) EGFR L858R–positive cases. The expression of female sex hormone receptors was not significantly different in clinicopathologically different subsets of lung ADC.
Conclusions
Expression of female sex hormone receptors is not associated with the prognosis and clinicopathological characteristics of patients with lung ADC.

Citations

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    Nuria Mederos, Alex Friedlaender, Solange Peters, Alfredo Addeo
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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
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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.

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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
Original Article
Serous Adenocarcinoma of Fallopian Tubes: Histological and Immunohistochemical Aspects
Natalia Hyriavenko, Mykola Lyndin, Kateryna Sikora, Artem Piddubnyi, Ludmila Karpenko, Olha Kravtsova, Dmytrii Hyriavenko, Olena Diachenko, Vladyslav Sikora, Anatolii Romaniuk
J Pathol Transl Med. 2019;53(4):236-243.   Published online April 11, 2019
DOI: https://doi.org/10.4132/jptm.2019.03.21
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AbstractAbstract PDF
Background
Although primary cancer of the fallopian tubes is a relatively rare type of tumor in female reproductive organs, its mortality is quite high. It is important to identify molecular and biological markers of this malignancy that determine its specific phenotype.
Methods
The study was carried out on samples received from 71 female patients with primary cancer of the fallopian tubes. The main molecular and biological properties, including hormone status (estrogen receptor [ER], progesterone receptor [PR]), human epidermal growth factor receptor (HER2)/neu expression, proliferative potential (Ki-67), apoptosis (p53, Bcl-2), and pro-angiogenic (vascular endothelial growth factor) quality of serous tumors were studied in comparison with clinical and morphological characteristics.
Results
ER and PR expression is accompanied by low grade neoplasia, early clinical disease stage, and absence of lymphogenic metastasis (p < .001). HER2/neu expression is not typical for primary cancer of the fallopian tubes. Ki-67 expression is characterized by an inverse correlation with ER and PR (p < .05) and is associated with lymphogenic metastasis (p < .01). p53+ status correlates with high grade malignancy, tumor progression, metastasis, negative ER/PR (p < .001), and negative Bcl-2 status (p < .05). Positive Bcl-2 status is positively correlated with ER and PR expression and low grade malignancy.
Conclusions
Complex morphologic (histological and immunohistochemical) study of postoperative material allows estimation of the degree of malignancy and tumor spread to enable appropriate treatment for each case.

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  • Rare non-serous fallopian tube cancers: institutional experience and literature review
    Dmitrii Sumtsov, Georgyi Sumtsov, Nataliia Hyriavenko, Mykola Lyndin, Kateryna Sikora, Nataliia Kalashnik, Svitlana Smiian, Igor Gladchuk
    Wiener Medizinische Wochenschrift.2024; 174(9-10): 199.     CrossRef
  • UŞAQLIQ BORULARININ BİRİNCİLİ XƏRÇƏNGİ: DİAQNOSTİKASI VƏ MÜALİCƏSİNİN NƏTİCƏLƏRİ
    D.G. Sumtsov, G.O. Sumtsov, N.I. Hyriavenko, S.A. Smiian, N.V. Kalashnyk, K.O. Sikora, N.M. Rozhkovska, I.Z. Gladchuk
    Azerbaijan Medical Journal.2023; (4): 75.     CrossRef
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    M. Lytvynenko
    Inter Collegas.2021; 8(1): 52.     CrossRef
  • Concurrent Clostridial Enteritis and Oviductal Adenocarcinoma with Carcinomatosis in an Adult Alpaca (Vicugna pacos)
    Mandy Womble, Megan E. Schreeg, Allison Hoch, Enoch B. de Souza Meira, Derek Foster, Christopher Premanandan, Tatiane T. Negrão Watanabe
    Journal of Comparative Pathology.2021; 189: 52.     CrossRef
  • Problems of primary fallopian tube cancer diagnostics during and after surgery
    D.G. Sumtsov, I.Z. Gladchuk, G.O. Sumtsov, N.I. Hyriavenko, M.S. Lyndin, V.V. Sikora, V.M. Zaporozhan
    REPRODUCTIVE ENDOCRINOLOGY.2021; (59): 66.     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
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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.

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    M.G.O. Fernandes, A.S. Vilariça, B. Fernandes, C. Camacho, C. Saraiva, F. Estevinho, H. Novais e Bastos, J.M. Lopes, P. Fidalgo, P. Garrido, S. Alves, S. Silva, T. Sequeira, F. Barata
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    Chiara Reina, Berina Šabanović, Chiara Lazzari, Vanesa Gregorc, Christopher Heeschen
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    Amaia Sandúa, Estibaliz Alegre, Álvaro González
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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
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    Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim
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    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
Potential Role for a Panel of Immunohistochemical Markers in the Management of Endometrial Carcinoma
Amany Salama, Mohammad Arafa, Eman ElZahaf, Abdelhadi Mohamed Shebl, Azmy Abd El-Hameed Awad, Sylvia A. Ashamallah, Reda Hemida, Anas Gamal, Abd AlRahman Foda, Khaled Zalata, El-Said M. Abdel-Hady
J Pathol Transl Med. 2019;53(3):164-172.   Published online February 28, 2019
DOI: https://doi.org/10.4132/jptm.2019.02.12
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AbstractAbstract PDF
Background
In order to improve the efficacy of endometrial carcinoma (EC) treatment, identifying prognostic factors for high risk patients is a high research priority. This study aimed to assess the relationships among the expression of estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and the different histopathological prognostic parameters in EC and to assess the value of these in the management of EC.
Methods
We examined 109 cases of EC. Immunohistochemistry for ER, PR, HER2, and Ki-67 were evaluated in relation to age, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and grade, depth of infiltration, cervical and ovarian involvement, lymphovascular space invasion (LVSI), and lymph node (LN) metastasis.
Results
The mean age of patients in this study was 59.8 ± 8.2 years. Low ER and PR expression scores and high Ki-67 expression showed highly significant associations with non-endometrioid histology (p = .007, p < .001, and p < .001, respectively) and poor differentiation (p = .007, p < .001, and p <. 001, respectively). Low PR score showed a significant association with advanced stage (p = .009). Low ER score was highly associated with LVSI (p = .006), and low PR scores were associated significantly with LN metastasis (p = .026). HER2 expression was significantly related to advanced stages (p = .04), increased depth of infiltration (p = .02), LVSI (p = .017), ovarian involvement (p = .038), and LN metastasis (p = .038). There was a close relationship between HER2 expression and uterine cervical involvement (p = .009). Higher Ki-67 values were associated with LN involvement (p = .012).
Conclusions
The over-expression of HER2 and Ki-67 and low expression of ER and PR indicate a more malignant EC behavior. An immunohistochemical panel for the identification of high risk tumors can contribute significantly to prognostic assessments.

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    Yingying Cao, Wei Zhang, Xiaorong Wang, Xiaojing Lv, Yaping Zhang, Kai Guo, Shuai Ren, Yuan Li, Zhongqiu Wang, Jingya Chen
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    Laura Paleari, Mariangela Rutigliani, Oriana D’Ecclesiis, Sara Gandini, Irene Maria Briata, Tania Buttiron Webber, Nicoletta Provinciali, Andrea DeCensi
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    European Journal of Obstetrics & Gynecology and Reproductive Biology: X.2022; 16: 100172.     CrossRef
  • Immunohistochemical Expression of Oestrogen and Epidermal Growth Factor Receptors in Endometrial Cancerous in Sudanese Patients
    Salwa Abdalraheem Abubaker, Mohamed Elfatih Abdelwadoud, Mutaz Mohamed Ali, Hadia Alhaj Ahmad, Abuobieda Mohamed Khlafalla, Osman Mohammed Elmahi, Hisham Ali Waggiallah
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    V. B. Shivkumar, Manisha A. Atram, Nitin M. Gangane
    Indian Journal of Gynecologic Oncology.2020;[Epub]     CrossRef
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    Rachana Lakhe, Ravi M Swami, Preeti Doshi, Manjiri N Karandikar, Ravindra Nimbargi
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Uterine Malignant Mixed Müllerian Tumors Following Treatment with Selective Estrogen Receptor Modulators in Patients with Breast Cancer: A Report of 13 Cases and Their Clinicopathologic Characteristics
Byung-Kwan Jeong, Chang O. Sung, Kyu-Rae Kim
J Pathol Transl Med. 2019;53(1):31-39.   Published online December 18, 2018
DOI: https://doi.org/10.4132/jptm.2018.11.16
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AbstractAbstract PDF
Background
Breast cancer treatment with selective estrogen receptor modulators (SERMs) increasesthe incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologiccharacteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discusspossible pathogenetic mechanisms.
Methods
Among 28,104 patients with breast cancer, clinicopathologicfeatures and incidence of uMMMT were compared between patients who underwentSERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period,incidence, dose, and duration of SERM treatment, as well as overall survival rate, were comparedfor patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMTvs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathologicalfindings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ,progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT.
Results
The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold).All patients with SERM were postmenopausal and received daily 20–40 mg SERM. CumulativeSERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologicfeatures, such as International Federation of Gynecology and Obstetrics stage andoverall survival, were not significantly different between patients with S-uMMMT and NS-uMMMTor between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available forimmunostaining exhibited strong overexpression/null expression of p53 protein and significantlyincreased ERβ expression in carcinomatous and sarcomatous components.
Conclusions
SERMtherapy seemingly increases risk of S-uMMMT development; however, clinicopathologic featureswere similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expressionmight be involved in the etiology of S-uMMMT.

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  • Uterine carcinosarcomas: A case series of 9 cases from a low-income country
    Boubacar Efared, Halidou Hamadou Koura, Aïchatou Balaraba Abani Bako, Idrissa Boubacar, Habiba Salifou Boureima, Garba Mahamadou, Hassan Nouhou
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    Susanna Leskela, Belen Pérez-Mies, Juan Manuel Rosa-Rosa, Eva Cristobal, Michele Biscuola, María L. Palacios-Berraquero, SuFey Ong, Xavier Matias-Guiu Guia, José Palacios
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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
  • 7,810 View
  • 301 Download
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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.

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Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients
Sung Joo Kim, Soyeon An, Jae Hoon Lee, Joo Young Kim, Ki-Byung Song, Dae Wook Hwang, Song Cheol Kim, Eunsil Yu, Seung-Mo Hong
J Pathol Transl Med. 2017;51(4):388-395.   Published online June 8, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.19
  • 6,893 View
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AbstractAbstract PDF
Background
Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients.
Methods
To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival.
Results
PR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5-year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses.
Conclusions
Loss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients.

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Basaloid Squamous Cell Carcinoma of the Head and Neck: Subclassification into Basal, Ductal, and Mixed Subtypes Based on Comparison of Clinico-pathologic Features and Expression of p53, Cyclin D1, Epidermal Growth Factor Receptor, p16, and Human Papillomavirus
Kyung-Ja Cho, Se Un Jeong, Sung Bae Kim, Sang-wook Lee, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim
J Pathol Transl Med. 2017;51(4):374-380.   Published online June 8, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.03
  • 14,919 View
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AbstractAbstract PDF
Background
Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma with distinct pathologic characteristics. The histogenesis of BSCC is not fully understood, and the cancer has been suggested to originate from a totipotent primitive cell in the basal cell layer of the surface epithelium or in the proximal duct of secretory glands.
Methods
Twenty-six cases of head and neck BSCC from Asan Medical Center, Seoul, Korea, reported during a 14-year-period were subclassified into basal, ductal, and mixed subtypes according to the expression of basal (cytokeratin [CK] 5/6, p63) or ductal markers (CK7, CK8/18). The cases were also subject to immunohistochemical study for CK19, p53, cyclin D1, epidermal growth factor receptor (EGFR), and p16 and to in situ hybridization for human papillomavirus (HPV), and the results were clinico-pathologically compared.
Results
Mixed subtype (12 cases) was the most common, and these cases showed hypopharyngeal predilection, older age, and higher expression of CK19, p53, and EGFR than other subtypes. The basal subtype (nine cases) showed frequent comedo-necrosis and high expression of cyclin D1. The ductal subtype (five cases) showed the lowest expression of p53, cyclin D1, and EGFR. A small number of p16- and/or HPV-positive cases were not restricted to one subtype. BSCC was the cause of death in 19 patients, and the average follow-up period for all patients was 79.5 months. Overall survival among the three subtypes was not significantly different.
Conclusions
The results of this study suggest a heterogeneous pathogenesis of head and neck BSCC. Each subtype showed variable histology and immunoprofiles, although the clinical implication of heterogeneity was not determined in this study.

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    Yinghong Zhang, Suqing Tian, Yali Du, Qiang Zuo, Li Zhu, Furong Ma
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  • Cetuximab and paclitaxel combination therapy for recurrent basaloid squamous cell carcinoma in the ethmoid sinus
    Satoshi Koyama, Kazunori Fujiwara, Tsuyoshi Morisaki, Taihei Fujii, Yosuke Nakamura, Takahiro Fukuhara, Hiromi Takeuchi
    Auris Nasus Larynx.2021; 48(6): 1189.     CrossRef
  • Constitutive Hedgehog/GLI2 signaling drives extracutaneous basaloid squamous cell carcinoma development and bone remodeling
    Marina Grachtchouk, Jianhong Liu, Mark E Hutchin, Paul W Harms, Dafydd Thomas, Lebing Wei, Aiqin Wang, Donelle Cummings, Lori Lowe, Jonathan Garlick, James Sciubba, Arul M Chinnaiyan, Monique E Verhaegen, Andrzej A Dlugosz
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  • Conjunctival ‘mucoepidermoid carcinoma’ revisited: a revision of terminology, based on morphologic, immunohistochemical and molecular findings of 14 cases, and the 2018 WHO Classification of Tumours of the Eye
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  • p53 and p16 expression in oral cavity squamous cell and basaloid squamous cell carcinoma
    Allisson Filipe Lopes Martins, Carlos Henrique Pereira, Marília Oliveira Morais, Paulo Otávio Carmo Souza, Lucas Borges Fleury Fernandes, Aline Carvalho Batista, Elismauro Francisco Mendonça
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Higher Expression of Toll-like Receptors 3, 7, 8, and 9 in Pityriasis Rosea
Mostafa Abou El-Ela, Mohamed El-Komy, Rania Abdel Hay, Rehab Hegazy, Amin Sharobim, Laila Rashed, Khalda Amr
J Pathol Transl Med. 2017;51(2):148-151.   Published online February 13, 2017
DOI: https://doi.org/10.4132/jptm.2016.09.09
  • 6,710 View
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  • 3 Web of Science
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AbstractAbstract PDF
Background
Pityriasis rosea (PR) is a common papulosquamous skin disease in which an infective agent may be implicated. Toll-like receptors (TLRs) play an important role in immune responses and in the pathophysiology of inflammatory skin diseases. Our aim was to determine the possible roles of TLRs 3, 7, 8, and 9 in the pathogenesis of PR. Methods: Twenty-four PR patients and 24 healthy individuals (as controls) were included in this case control study. All recruits were subjected to routine laboratory investigations. Biopsies were obtained from one active PR lesion and from healthy skin of controls for the detection of TLR 3, 7, 8, and 9 gene expression using real-time polymerase chain reaction. Results: This study included 24 patients (8 females and 16 males) with active PR lesions, with a mean age of 28.62 years. Twenty four healthy age- and sex-matched individuals were included as controls (8 females and 16 males, with a mean age of 30.83 years). The results of the routine laboratory tests revealed no significant differences between both groups. Significantly elevated expression of all studied TLRs were detected in PR patients relative to healthy controls (p < .001). Conclusions: TLRs 3, 7, 8, and 9 might be involved in the pathogenesis of PR.

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    Alexander K.C. Leung, Joseph M. Lam, Kin Fon Leong, Kam Lun Hon
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