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Exploring histological predictive biomarkers for immune checkpoint inhibitor therapy response in non–small cell lung cancer
Uiju Cho, Soyoung Im, Hyung Soon Park
J Pathol Transl Med. 2024;58(2):49-58.   Published online February 26, 2024
DOI: https://doi.org/10.4132/jptm.2024.01.31
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AbstractAbstract PDF
Treatment challenges persist in advanced lung cancer despite the development of therapies beyond the traditional platinum-based chemotherapy. The early 2000s marked a shift to tyrosine kinase inhibitors targeting epidermal growth factor receptor, ushering in personalized genetic-based treatment. A further significant advance was the development of immune checkpoint inhibitors (ICIs), especially for non–small cell lung cancer. These target programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4, which enhanced the immune response against tumor cells. However, not all patients respond, and immune-related toxicities arise. This review emphasizes identifying biomarkers for ICI response prediction. While PD-L1 is a widely used, validated biomarker, its predictive accuracy is imperfect. Investigating tumor-infiltrating lymphocytes, tertiary lymphoid structure, and emerging biomarkers such as high endothelial venule, Human leukocyte antigen class I, T-cell immunoreceptors with Ig and ITIM domains, and lymphocyte activation gene-3 counts is promising. Understanding and exploring additional predictive biomarkers for ICI response are crucial for enhancing patient stratification and overall care in lung cancer treatment.
Biomarker testing of cytology specimens in personalized medicine for lung cancer patients
Hyojin Kim, Jin-Haeng Chung
J Pathol Transl Med. 2022;56(6):326-333.   Published online November 9, 2022
DOI: https://doi.org/10.4132/jptm.2022.10.17
  • 1,630 View
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AbstractAbstract PDF
Every patient with advanced non–small cell lung cancer (NSCLC) should be tested for targetable driver mutations and gene arrangements that may open avenues for targeted therapy. As most patients with NSCLC in the advanced stage of the disease are not candidates for surgery, these tests have to be performed on small biopsies or cytology samples. A growing number of other genetic changes with targetable mutations may be treatable in the near future. To identify patients who might benefit from novel targeted therapy, relevant markers should be tested in an appropriate context. In addition, immunotherapy of lung cancer is guided by the status of programmed death-ligand 1 expression in tumor cells. The variety and versatility of cytological specimen preparations offer significant advantages for molecular testing; however, they frequently remain underused. Therefore, evaluating the utility and adequacy of cytologic specimens is important, not only from a lung cancer diagnosis, but also for the large number of ancillary studies that are necessary to provide appropriate clinical management. A large proportion of lung cancers is diagnosed by aspiration or exfoliative cytology specimens; thus, optimizing strategies to triage and best use the tissue for diagnosis and biomarker studies forms a critical component of lung cancer management. In this review, we discuss the opportunities and challenges of using cytologic specimens for biomarker testing of lung cancer and the role of cytopathology in the molecular era.

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  • Molecular testing of cytology specimens: Issues in specimen adequacy and clinical utility
    Ghulam Ghous, Komal Ijaz, Magda Esebua, Lester J. Layfield
    Diagnostic Cytopathology.2024; 52(2): 123.     CrossRef
Original Articles
Usefulness of BRAF VE1 immunohistochemistry in non–small cell lung cancers: a multi-institutional study by 15 pathologists in Korea
Sunhee Chang, Yoon-La Choi, Hyo Sup Shim, Geon Kook Lee, Seung Yeon Ha
J Pathol Transl Med. 2022;56(6):334-341.   Published online October 27, 2022
DOI: https://doi.org/10.4132/jptm.2022.08.22
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  • 127 Download
  • 5 Web of Science
  • 4 Crossref
AbstractAbstract PDF
Background
Next-generation sequencing (NGS) is an approved test to select patients for BRAF V600E targeted therapy in Korea. However, the high cost, long turnaround times, and the need for sophisticated equipment and skilled personnel limit the use of NGS in daily practice. Immunohistochemistry (IHC) is a rapid and relatively inexpensive assay available in most laboratories. Therefore, in this study, we evaluate the usefulness of BRAF VE1 IHC in terms of predictive value and interobserver agreement in non–small cell lung cancers (NSCLCs).
Methods
A total of 30 cases with known BRAF mutation status were selected, including 20 cases of lung adenocarcinomas, six cases of colorectal adenocarcinomas, and four cases of papillary thyroid carcinomas. IHC for BRAF V600E was carried out using the VE1 antibody. Fifteen pathologists independently scored both the staining intensity and the percentage of tumor cell staining on whole slide images.
Results
In the lung adenocarcinoma subset, interobserver agreement for the percentage of tumor cell staining and staining intensity was good (percentage of tumor cell staining, intraclass correlation coefficient = 0.869; staining intensity, kappa = 0.849). The interobserver agreement for the interpretation using the cutoff of 40% was almost perfect in the entire study group and the lung adenocarcinoma subset (kappa = 0.815). Sensitivity, specificity, positive predictive value, and negative predictive value of BRAF VE1 IHC were 80.0%, 90.0%, 88.9%, and 81.8%, respectively.
Conclusions
BRAF VE1 IHC could be a screening test for the detection of BRAF V600E mutation in NSCLC. However, further studies are needed to optimize the protocol and to establish and validate interpretation criteria for BRAF VE1 IHC.

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  • Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review
    Suyeon Kim, Hyunsik Bae, Hyun-Soo Kim
    Diagnostics.2024; 14(2): 160.     CrossRef
  • Differentiating BRAF V600E- and RAS-like alterations in encapsulated follicular patterned tumors through histologic features: a validation study
    Chankyung Kim, Shipra Agarwal, Andrey Bychkov, Jen-Fan Hang, Agnes Stephanie Harahap, Mitsuyoshi Hirokawa, Kennichi Kakudo, Somboon Keelawat, Chih-Yi Liu, Zhiyan Liu, Truong Phan-Xuan Nguyen, Chanchal Rana, Huy Gia Vuong, Yun Zhu, Chan Kwon Jung
    Virchows Archiv.2024;[Epub]     CrossRef
  • BRAF V600E Mutation of Non-Small Cell Lung Cancer in Korean Patients
    Hyo Yeong Ahn, Chang Hun Lee, Min Ki Lee, Jung Seop Eom, Yeon Joo Jeong, Yeong Dae Kim, Jeong Su Cho, Jonggeun Lee, So Jeong Lee, Dong Hoon Shin, Ahrong Kim
    Medicina.2023; 59(6): 1085.     CrossRef
  • Reevaluating diagnostic categories and associated malignancy risks in thyroid core needle biopsy
    Chan Kwon Jung
    Journal of Pathology and Translational Medicine.2023; 57(4): 208.     CrossRef
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
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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.
Case Studies
Primary pulmonary epithelioid inflammatory myofibroblastic sarcoma: a rare entity and a literature review
Priyanka Singh, Aruna Nambirajan, Manish Kumar Gaur, Rahul Raj, Sunil Kumar, Prabhat Singh Malik, Deepali Jain
J Pathol Transl Med. 2022;56(4):231-237.   Published online July 7, 2022
DOI: https://doi.org/10.4132/jptm.2022.05.08
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AbstractAbstract PDF
Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of inflammatory myofibroblastic tumor (IMT) harboring anaplastic lymphoma kinase (ALK) gene fusions and is associated with high risk of local recurrence and poor prognosis. Herein, we present a young, non-smoking male who presented with complaints of cough and dyspnoea and was found to harbor a large right lower lobe lung mass. Biopsy showed a high-grade epithelioid to rhabdoid tumor with ALK and desmin protein expression. The patient initially received 5 cycles of crizotinib and remained stable for 1 year; however, he then developed multiple bony metastases, for which complete surgical resection was performed. Histopathology confirmed the diagnosis of EIMS, with ALK gene rearrangement demonstrated by fluorescence in situ hybridization. Postoperatively, the patient is asymptomatic with stable metastatic disease on crizotinib and has been started on palliative radiotherapy. EIMS is a very rare subtype of IMT that needs to be included in the differential diagnosis of ALKexpressing lung malignancies in young adults.

Citations

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  • Mediastinal epithelioid inflammatory myofibroblastic sarcoma with the EML4‐ALK fusion: A case report and literature review
    Tingyu Pan, Xinyu Sun, Xiao Wu, Futing Tang, Xianmei Zhou, Qian Wang, Shi Chen
    Respirology Case Reports.2024;[Epub]     CrossRef
  • Case report: Epithelioid inflammatory myofibroblastic sarcoma treated with an ALK TKI ensartinib
    Mengmeng Li, Ruyue Xing, Jiuyan Huang, Chao Shi, Chunhua Wei, Huijuan Wang
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Epithelioid Inflammatory Myofibroblastic Sarcoma With Poor Response to Crizotinib: A Case Report
    Soheila Aminimoghaddam, Roghayeh Pourali
    Clinical Medicine Insights: Case Reports.2023;[Epub]     CrossRef
  • Epithelioid inflammatory myofibroblastic sarcoma: a case report and brief literature review
    Weidong Dou, Yu Guan, Tao Liu, Hang Zheng, Shuo Feng, Yingchao Wu, Xin Wang, Zhanbing Liu
    Frontiers in Oncology.2023;[Epub]     CrossRef
TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma
Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta
J Pathol Transl Med. 2022;56(1):53-56.   Published online November 16, 2021
DOI: https://doi.org/10.4132/jptm.2021.09.16
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AbstractAbstract PDF
SMARCA4/BRG1-deficient lung adenocarcinoma (SD-LUAD) is being recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other non–small cell lung carcinomas. We present here a case of SD-LUAD with curious thyroid transcription factor 1 (TTF1) expression in a morphologically heterogenous lung adenocarcinoma. The better differentiated area showed preservation of TTF1 expression, and a poorly differentiated tumor had loss of TTF1 expression with universal BRG1 loss.

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  • Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma
    Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
    World Journal of Clinical Cases.2022; 10(29): 10501.     CrossRef
  • Novel germline SMARCA4 mutation in Small Cell Carcinoma of the Ovary, Hypercalcemic Type
    Anurag Mehta, Himanshi Diwan, Diksha Karki, Divya Bansal, Meenakshi Kamboj, Anila Sharma, Shrinidhi Nathany, Sakshi Mattoo, Dushyant Kumar
    Current Problems in Cancer: Case Reports.2022; 8: 100205.     CrossRef
Original Articles
Programmed death-ligand 1 expression and tumor-infiltrating lymphocytes in non-small cell lung cancer: association with clinicopathologic parameters
Gaurav Garg, Kuruswamy Thurai Prasad, Navneet Singh, Parul Gupta, Valliappan Muthu, Ashim Das, Amanjit Bal
J Pathol Transl Med. 2021;55(6):398-405.   Published online October 6, 2021
DOI: https://doi.org/10.4132/jptm.2021.08.08
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AbstractAbstract PDFSupplementary Material
Background
Data on the prevalence of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in non–small cell lung cancer (NSCLC) and their clinical significance in Indian patients are limited.
Methods
Newly diagnosed NSCLC cases (adenocarcinoma or squamous cell carcinoma [SqCC] histology) were included in the present study. The TILs were evaluated based on morphology on hematoxylin and eosin–stained slides. PD-L1 expression in tumors was assessed using immunohistochemistry with rabbit monoclonal antibody (SP263) on the Ventana automated immunostainer. Tumors with PD-L1 expression > 50% on tumor cells were considered PD-L1–positive. Tumors in which TILs occupy > 25% of stroma were considered to have high TILs. The association of PD-L1 expression and TILs with various clinical parameters including overall survival (OS) was investigated.
Results
The present study included 128 cases of NSCLC (67 adenocarcinoma, 61 SqCC). PD-L1 positivity was observed in 17.2% of the patients with NSCLC. Baseline characteristics of PD-L1–positive subjects were similar to PD-L1–negative subjects except for a higher prevalence of liver metastasis (18.2% vs. 2.8%; p = .018) and a higher probability of diagnosis from extrapulmonary biopsies. High TILs were observed in 26.6% of the subjects. However, PD-L1 expression and high TIL did not affect OS.
Conclusions
PD-L1 positivity and high TILs were observed in 20% and 25% of the patients with NSCLC, respectively, however, neither were predictors of survival in SqCC.

Citations

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  • Real-world prevalence of PD-L1 expression in non-small cell lung cancer: an Australia-wide multi-centre retrospective observational study
    Prudence A. Russell, Alexandra L. Farrall, Sarita Prabhakaran, Khashayar Asadi, Wade Barrett, Caroline Cooper, Wendy Cooper, Samuel Cotton, Edwina Duhig, Matthew Egan, Stephen Fox, David Godbolt, Shilpa Gupta, Aniza Hassan, Connull Leslie, Trishe Leong, D
    Pathology.2023; 55(7): 922.     CrossRef
Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non–small cell lung cancer patients in resource constrained community hospitals
Anurag Mehta, Shrinidhi Nathany, Aanchal Chopra, Sakshi Mattoo, Dushyant Kumar, Manoj Kumar Panigrahi
J Pathol Transl Med. 2021;55(5):324-329.   Published online September 2, 2021
DOI: https://doi.org/10.4132/jptm.2021.07.15
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AbstractAbstract PDF
Background
A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as “MET exon 14 skipping” (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing.
Methods
This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives.
Results
Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained.
Conclusions
Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.

Citations

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  • MET: A narrative review of exon 14 skipping mutation in non-small-cell lung carcinoma
    Shrinidhi Nathany, Ullas Batra
    Cancer Research, Statistics, and Treatment.2022; 5(2): 284.     CrossRef
Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non–small cell lung carcinoma
Tripti Nakra, Varsha Singh, Aruna Nambirajan, Prabhat Singh Malik, Anant Mohan, Deepali Jain
J Pathol Transl Med. 2021;55(4):279-288.   Published online July 8, 2021
DOI: https://doi.org/10.4132/jptm.2021.05.10
  • 3,493 View
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  • 3 Web of Science
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AbstractAbstract PDF
Background
Thyroid transcription factor (TTF-1) is a diagnostic marker expressed in 75%–85% of primary lung adenocarcinomas (ACs). Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is the most common targetable driver alteration in lung AC. Previous studies have shown a positive correlation between TTF-1 and EGFR mutation status. We aimed to determine the predictive value of TTF-1 immunoexpression for underlying EGFR mutation status in a large Indian cohort.
Methods
This retrospective designed study was conducted with medical record data from 2011 to 2020. All cases of primary lung AC and non–small cell lung carcinoma not otherwise specified (NSCLC, NOS) with known TTF-1 expression diagnosed by immunohistochemistry using 8G7G3/1 antibodies and EGFR mutation status diagnosed by quantitative polymerase chain reaction were retrieved, reviewed, and the
results
were analyzed. Results: Among 909 patient samples diagnosed as lung AC and NSCLC, NOS, TTF-1 was positive in 76.8% cases (698/909) and EGFR mutations were detected in 29.6% (269/909). A strong positive correlation was present between TTF-1 positivity and EGFR mutation status (odds ratio, 3.61; p < .001), with TTF-1 positivity showing high sensitivity (90%) and negative predictive value (87%) for EGFR mutation. TTF-1 immunoexpression did not show significant correlation with uncommon/dual EGFR mutations (odds ratio, 1.69; p = .098). EGFR–tyrosine kinase inhibitor therapy was significantly superior to chemotherapy among EGFR mutant cases irrespective of TTF-1 status; however, no significant differences among survival outcomes were observed.
Conclusions
Our study confirms a strong positive correlation between TTF-1 expression and common EGFR mutations (exon 19 deletion and exon 21 L858R) in advanced lung AC with significantly high negative predictive value of TTF-1 for EGFR mutations.

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  • Mutation profile and programmed death ligand 1 status of patients with non‐small cell lung cancer diagnosed with “adenocarcinoma” and “non‐small cell carcinoma favor adenocarcinoma”
    Naoko Shigeta, Tomoyuki Yokose, Shuji Murakami, Tetsuya Isaka, Kanako Shinada, Emi Yoshioka, Atsuya Narita, Kengo Katakura, Tetsuro Kondo, Terufumi Kato, Takuya Nagashima, Haruhiro Saito, Hiroyuki Ito
    Thoracic Cancer.2024; 15(6): 458.     CrossRef
  • Expression landscapes in non-small cell lung cancer shaped by the thyroid transcription factor 1
    Herdee Gloriane C. Luna, Marcelo Severino Imasa, Necy Juat, Katherine V. Hernandez, Treah May Sayo, Gloria Cristal-Luna, Sheena Marie Asur-Galang, Mirasol Bellengan, Kent John Duga, Bien Brian Buenaobra, Marvin I. De los Santos, Daniel Medina, Jamirah Sam
    Lung Cancer.2023; 176: 121.     CrossRef
  • Malignant pleural effusion cell blocks are reliable resources for PD-L1 analysis in advanced lung adenocarcinomas: a concordance study with matched histologic samples
    Swati Mahajan, Aruna Nambirajan, Ishan Gupta, Nalini Gupta, Parikshaa Gupta, Deepali Jain
    Journal of the American Society of Cytopathology.2022; 11(5): 253.     CrossRef
  • Clinicopathologic Features and Molecular Biomarkers as Predictors of Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer Patients
    Lanlan Liu, Xianzhi Xiong
    Current Oncology.2021; 29(1): 77.     CrossRef
SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer
Anurag Mehta, Divya Bansal, Rupal Tripathi, Ankush Jajodia
J Pathol Transl Med. 2021;55(5):307-316.   Published online June 21, 2021
DOI: https://doi.org/10.4132/jptm.2021.05.11
  • 5,806 View
  • 279 Download
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AbstractAbstract PDF
Background
SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.
Methods
All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases.
Results
Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.
Conclusions
It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Citations

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  • Case report: The first account of undifferentiated sarcoma with epithelioid features originating in the pleura
    Ling-Xi Xiao, Li Liu, Wang Deng
    Frontiers in Medicine.2024;[Epub]     CrossRef
  • Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature
    Akriti Pokhrel, Ruchi Yadav, Kapil Kumar Manvar, Richard Wu, Vijay Jaswani, Carrie Brooke Wasserman, Jen C. Wang
    Journal of Investigative Medicine High Impact Case Reports.2023; 11: 232470962311762.     CrossRef
  • TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma
    Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta
    Journal of Pathology and Translational Medicine.2022; 56(1): 53.     CrossRef
  • Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma
    Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
    World Journal of Clinical Cases.2022; 10(29): 10501.     CrossRef
  • Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors
    Joseph McDermott, Drew Sturtevant, Umesh Kathad, Sudhir Varma, Jianli Zhou, Aditya Kulkarni, Neha Biyani, Caleb Schimke, William C. Reinhold, Fathi Elloumi, Peter Carr, Yves Pommier, Kishor Bhatia
    Frontiers in Drug Discovery.2022;[Epub]     CrossRef
Review
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
J Pathol Transl Med. 2021;55(3):181-191.   Published online May 11, 2021
DOI: https://doi.org/10.4132/jptm.2021.03.23
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AbstractAbstract PDF
Molecular biomarker testing is the standard of care for non–small cell lung cancer (NSCLC) patients. In 2017, the Korean Cardiopulmonary Pathology Study Group and the Korean Molecular Pathology Study Group co-published a molecular testing guideline which contained almost all known genetic changes that aid in treatment decisions or predict prognosis in patients with NSCLC. Since then there have been significant changes in targeted therapies as well as molecular testing including newly approved targeted drugs and liquid biopsy. In order to reflect these changes, the Korean Cardiopulmonary Pathology Study Group developed a consensus statement on molecular biomarker testing. This consensus statement was crafted to provide guidance on what genes should be tested, as well as methodology, samples, patient selection, reporting and quality control.

Citations

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  • Clinical utility of the Oncomine Dx Target Test multi‐CDx system and the possibility of utilizing those original sequence data
    Ayaka Saito, Hideki Terai, Tae‐Jung Kim, Katsura Emoto, Ryutaro Kawano, Kohei Nakamura, Hideyuki Hayashi, Hatsuyo Takaoka, Akihiko Ogata, Katsuhito Kinoshita, Fumimaro Ito, Lisa Shigematsu, Masahiko Okada, Takahiro Fukushima, Akifumi Mitsuishi, Taro Shino
    Cancer Medicine.2024;[Epub]     CrossRef
  • FACILITATE: A real-world, multicenter, prospective study investigating the utility of a rapid, fully automated real-time PCR assay versus local reference methods for detecting epidermal growth factor receptor variants in NSCLC
    Anke Behnke, Anne Cayre, Giovanna De Maglio, Giuseppe Giannini, Lionel Habran, Marina Tarsitano, Massimiliano Chetta, David Cappellen, Alexandra Lespagnol, Cecile Le Naoures, Gabriella Massazza, Annarita Destro, Irina Bonzheim, Achim Rau, Achim Battmann,
    Pathology and Oncology Research.2023;[Epub]     CrossRef
  • Problems in the Pathologic Diagnosis of Suspected Lung Cancer
    Soo Han Kim, Mi-Hyun Kim, Min Ki Lee, Jung Seop Eom
    Tuberculosis and Respiratory Diseases.2023; 86(3): 176.     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
  • 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
  • Biomarker testing of cytology specimens in personalized medicine for lung cancer patients
    Hyojin Kim, Jin-Haeng Chung
    Journal of Pathology and Translational Medicine.2022; 56(6): 326.     CrossRef
  • Usefulness of BRAF VE1 immunohistochemistry in non–small cell lung cancers: a multi-institutional study by 15 pathologists in Korea
    Sunhee Chang, Yoon-La Choi, Hyo Sup Shim, Geon Kook Lee, Seung Yeon Ha
    Journal of Pathology and Translational Medicine.2022; 56(6): 334.     CrossRef
  • Lung Cancer in Korea
    Sehhoon Park, Chang-Min Choi, Seung-Sik Hwang, Yoon-La Choi, Hyae Young Kim, Young-Chul Kim, Young Tae Kim, Ho Yun Lee, Si Yeol Song, Myung-Ju Ahn
    Journal of Thoracic Oncology.2021; 16(12): 1988.     CrossRef
Case Study
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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  • 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.

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    Pathology and Oncology Research.2023;[Epub]     CrossRef
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Review
Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma
In Ae Kim, Jae Young Hur, Hee Joung Kim, Seung Eun Lee, Wan Seop Kim, Kye Young Lee
J Pathol Transl Med. 2020;54(6):453-461.   Published online October 8, 2020
DOI: https://doi.org/10.4132/jptm.2020.08.13
  • 4,843 View
  • 153 Download
  • 12 Web of Science
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AbstractAbstract PDF
Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.

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  • Nanobiotechnology: A smart platform of the future transform liquid biopsy era
    Srijan Goswami, Palas Samanta, Manab Deb Adhikari
    The Journal of Liquid Biopsy.2024; 3: 100137.     CrossRef
  • Extracellular Vesicle-DNA: The Next Liquid Biopsy Biomarker for Early Cancer Diagnosis?
    Irène Tatischeff
    Cancers.2023; 15(5): 1456.     CrossRef
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    Migmar Tsamchoe, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos
    Biotechnology Journal.2023;[Epub]     CrossRef
  • The role of extracellular vesicles in non-small-cell lung cancer, the unknowns, and how new approach methodologies can support new knowledge generation in the field
    Sive Mullen, Dania Movia
    European Journal of Pharmaceutical Sciences.2023; 188: 106516.     CrossRef
  • Silicon microfabrication technologies for biology integrated advance devices and interfaces
    Vuslat B. Juska, Graeme Maxwell, Pedro Estrela, Martyn E. Pemble, Alan O'Riordan
    Biosensors and Bioelectronics.2023; 237: 115503.     CrossRef
  • Bronchoalveolar Lavage as Potential Diagnostic Specimens to Genetic Testing in Advanced Nonsmall Cell Lung Cancer
    Xuwen Lin, Yazhou Cai, Chenyu Zong, Binbin Chen, Di Shao, Hao Cui, Zheng Li, Ping Xu
    Technology in Cancer Research & Treatment.2023;[Epub]     CrossRef
  • In-Cell Labeling Coupled to Direct Analysis of Extracellular Vesicles in the Conditioned Medium to Study Extracellular Vesicles Secretion with Minimum Sample Processing and Particle Loss
    Anissa Viveiros, Vaibhavi Kadam, John Monyror, Luis Carlos Morales, Desmond Pink, Aja M. Rieger, Simonetta Sipione, Elena Posse de Chaves
    Cells.2022; 11(3): 351.     CrossRef
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    Zhixian Chen, Judy Wai Ping Yam
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    Cristina Catoni, Veronica Di Paolo, Elisabetta Rossi, Luigi Quintieri, Rita Zamarchi
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    Susana García-Silva, Miguel Gallardo, Héctor Peinado
    Frontiers in Cell and Developmental Biology.2021;[Epub]     CrossRef
  • Characteristics and Clinical Application of Extracellular Vesicle-Derived DNA
    Jae Young Hur, Kye Young Lee
    Cancers.2021; 13(15): 3827.     CrossRef
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    Xuwen Lin, Xueying Wang, Yazhou Cai, Chenyu Zong, Dawei Liu, Jiming Yu, Chenxin Zhou, Jing Yao, Zheng Li, ping xu
    SSRN Electronic Journal .2021;[Epub]     CrossRef
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Original Articles
Analysis of PAX8 immunohistochemistry in lung cancers: a meta-analysis
Jae Han Jeong, Nae Yu Kim, Jung-Soo Pyo
J Pathol Transl Med. 2020;54(4):300-309.   Published online July 10, 2020
DOI: https://doi.org/10.4132/jptm.2020.06.08
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AbstractAbstract PDF
Background
In this meta-analysis, we aimed to evaluate the PAX8 immunohistochemical expressions in primary lung cancers and metastatic cancers to the lung.
Methods
We identified and reviewed relevant articles from the PubMed databases. Ultimately, 18 articles were included in this meta-analysis. PAX8 expression rates were analyzed and compared between primary and metastatic lung cancers.
Results
The PAX8 expression rate in primary lung cancers was 0.042 (95% confidence interval [CI], 0.025 to 0.071). PAX8 expression rates of small cell (0.129; 95% CI, 0.022 to 0.496) and non-small cell carcinomas of the lung (0.037; 95% CI, 0.022 to 0.061) were significantly different (p=.049 in a meta-regression test). However, the PAX8 expression rates of adenocarcinoma (0.013; 95% CI, 0.006 to 0.031) and squamous cell carcinoma (0.040; 95% CI, 0.016 to 0.097) were not significantly different. PAX8 expression rates of metastatic carcinomas to the lung varied, ranging from 1.8% to 94.9%. Metastatic carcinomas from the lung to other organs had a PAX8 expression rate of 6.3%. The PAX8 expression rates of metastatic carcinomas from the female genital organs, kidneys, and thyroid gland to the lung were higher than those of other metastatic carcinomas.
Conclusions
Primary lung cancers had a low PAX8 expression rate regardless of tumor subtype. However, the PAX8 expression rates of metastatic carcinomas from the female genital organs, kidneys, and thyroid were significantly higher than those of primary lung cancers.

Citations

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  • Prognostic value of PAX8 in small cell lung cancer
    Fengyun Tao, Hangyan Zhu, Jiayun Xu, Yanan Guo, Xin Wang, Lei Shao, Deng Pan, Guosheng Li, Rong Fang
    Heliyon.2024; : e28251.     CrossRef
  • Immunocytochemistry of effusions: Processing and commonly used immunomarkers
    Vinod B. Shidham, Beata Janikowski
    Cytojournal.2022; 19: 6.     CrossRef
  • Significance analysis of PAX8 expression in endometrial carcinoma
    Shan Hu, Hua Gan, Fengmei Yang
    Medicine.2022; 101(42): e31159.     CrossRef
Peripheral type squamous cell carcinoma of the lung: clinicopathologic characteristics in comparison to the central type
Yeoun Eun Sung, Uiju Cho, Kyo Young Lee
J Pathol Transl Med. 2020;54(4):290-299.   Published online June 17, 2020
DOI: https://doi.org/10.4132/jptm.2020.05.04
  • 5,128 View
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AbstractAbstract PDF
Background
Squamous cell carcinomas (SqCCs) of the lung are known to arise more often in a central area but reports of peripheral SqCCs have increased, with a pathogenesis that is obscured. In this study, the clinicopathologic characteristics of peripheral lung SqCCs were studied and compared with those of the central type.
Methods
This study included 63 peripheral lung SqCCs and 48 randomly selected central cases; hematoxylin and eosin-stained slides of surgically resected specimens were reviewed in conjunction with radiologic images and clinical history. Cytokeratin-7 immunohistochemical staining of key slides and epidermal growth factor receptor (EGFR)/KRAS mutations tested by DNA sequencing were also included.
Results
Stages of peripheral SqCCs were significantly lower than central SqCCs (p=.016). Cystic change of the mass (p=.007), presence of interstitial fibrosis (p=0.007), and anthracosis (p=.049) in the background lung were significantly associated with the peripheral type. Cytokeratin-7 positivity was also higher in peripheral SqCCs with cutoffs of both 10% and 50% (p=.011). Pathogenic mutations in EGFR and KRAS were observed in only one case out of the 72 evaluated. The Cox proportional hazard model indicated a significantly better disease-free survival (p=.009) and the tendency of better overall survival (p=.106) in the peripheral type.
Conclusions
In peripheral type, lower stage is a favorable factor for survival but more frequent interstitial fibrosis and older age are unfavorable factors. Multivariate Cox analysis revealed that peripheral type is associated with better disease-free survival. The pathogenesis of peripheral lung SqCCs needs further investigation, together with consideration of the background lung conditions.

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    Ryusuke Sumiya, Masayoshi Terayama, Teruki Hagiwara, Kazuaki Nakata, Keigo Sekihara, Satoshi Nagasaka, Hideki Miyazaki, Toru Igari, Kazuhiko Yamada, Yuki I. Kawamura
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    Xueqi Xie, Xiaolin Li, Wenjie Tang, Peng Xie, Xuefen Tan
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J Pathol Transl Med : Journal of Pathology and Translational Medicine