Journal of Pathology and Translational Medicine

Review

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

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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
The updated College of American Pathologists principles of analytic validation of immunohistochemical assays: A step forward for cytopathology
Sinchita Roy‐Chowdhuri
Cancer Cytopathology.2024;[Epub] CrossRef
Best-Practice Biomarker Testing of Oesophago-Gastric Cancer in the UK: Expert Consensus Recommendations Developed Using a Modified Delphi
N.P. West, W. Mansoor, P. Taniere, E. Smyth, M. Rodriguez-Justo, A. Oniscu, P. Carter
Clinical Oncology.2024; 36(11): 701. 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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Abstract PDF Supplementary 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.

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Multiplex plasma protein assays as a diagnostic tool for lung cancer
Mohammad Tanvir Ahamed, Jenny Forshed, Adrian Levitsky, Janne Lehtiö, Amanj Bajalan, Maria Pernemalm, Lars E. Eriksson, Björn Andersson
Cancer Science.2024; 115(10): 3439. CrossRef
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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Abstract 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.

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MET
Shrinidhi Nathany, Ullas Batra
Cancer Research, Statistics, and Treatment.2022; 5(2): 284. 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

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Abstract 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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Pulmonary squamous cell carcinoma and lymphoepithelial carcinoma – morphology, molecular characteristics and differential diagnosis
Sabina Berezowska, Marie Maillard, Mark Keyter, Bettina Bisig
Histopathology.2024; 84(1): 32. CrossRef
Assessment of seasonal variability of PM, BC and UFP levels at a highway toll stations and their associated health risks
Nazneen, Aditya Kumar Patra, Soma Sekhara Rao Kolluru, Abhishek Penchala, Sachidanand Kumar, Namrata Mishra, Naragam Bhanu Sree, Samrat Santra, Ravish Dubey
Environmental Research.2024; 245: 118028. CrossRef
Association between Airport Ultrafine Particles and Lung Cancer Risk: The Multiethnic Cohort Study
Arthur Bookstein, Justine Po, Chiuchen Tseng, Timothy V. Larson, Juan Yang, Sung-shim L. Park, Jun Wu, Salma Shariff-Marco, Pushkar P. Inamdar, Ugonna Ihenacho, Veronica W. Setiawan, Mindy C. DeRouen, Loïc Le Marchand, Daniel O. Stram, Jonathan Samet, Bea
Cancer Epidemiology, Biomarkers & Prevention.2024; 33(5): 703. CrossRef
Clinical and Bronchoscopy Assessment in Diagnosing the Histopathology Type of Primary Central Lung Tumors
Mia Elhidsi, Jamal Zaini, Lisnawati Rachmadi, Asmarinah Asmarinah, Aria Kekalih, Noni Soeroso, Menaldi Rasmin
The Open Respiratory Medicine Journal.2024;[Epub] CrossRef
Possible thoracic metastasis from squamous cell carcinoma of the external auditory canal: A case report
Hiroshi Takehara, Ken Kodama, Toru Momozane, Masashi Takeda, Kaichi Shigetsu, Hiroki Kishima
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Radiological precursor lesions of lung squamous cell carcinoma: Early progression patterns and divergent volume doubling time between hilar and peripheral zones
Haruto Sugawara, Yasushi Yatabe, Hirokazu Watanabe, Hiroyuki Akai, Osamu Abe, Shun-ichi Watanabe, Masahiko Kusumoto
Lung Cancer.2023; 176: 31. CrossRef
Loss of GSTO2 contributes to cell growth and mitochondria function via the p38 signaling in lung squamous cell carcinoma
Ryusuke Sumiya, Masayoshi Terayama, Teruki Hagiwara, Kazuaki Nakata, Keigo Sekihara, Satoshi Nagasaka, Hideki Miyazaki, Toru Igari, Kazuhiko Yamada, Yuki I. Kawamura
Cancer Science.2022; 113(1): 195. CrossRef
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Xueqi Xie, Xiaolin Li, Wenjie Tang, Peng Xie, Xuefen Tan
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Pulmonary squamous cell carcinoma with a lepidic-pagetoid growth pattern
Claudio Guerrieri, Mark Lindner, Joanna Sesti, Abhishek Chakraborti, Rachel Hudacko
Pathologica.2022; 114(4): 304. CrossRef
Deposition modeling of ambient particulate matter in the human respiratory tract
Salman Khan, Bhola Ram Gurjar, Veerendra Sahu
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Selection of the surgical approach for patients with cStage IA lung squamous cell carcinoma: A population-based propensity score matching analysis
Shengteng Shao, Guisong Song, Yuanyong Wang, Tengfei Yi, Shuo Li, Fuhui Chen, Yang Li, Xiaotong Liu, Bin Han, Yuhong Liu
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Gene variant profiles and tumor metabolic activity as measured by FOXM1 expression and glucose uptake in lung adenocarcinoma: Ashley Goodman, Waqas Mahmud, Lela Buckingham; J Pathol Transl Med. 2020;54(3):237-245. Published online March 4, 2020; DOI: https://doi.org/10.4132/jptm.2020.02.08

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Abstract PDF

Background
Cancer cells displaying aberrant metabolism switch energy production from oxidative phosphorylation to glycolysis. Measure of glucose standardized uptake value (SUV) by positron emission tomography (PET), used for staging of adenocarcinoma in high-risk patients, can reflect cellular use of the glycolysis pathway. The transcription factor, FOXM1 plays a role in regulation of glycolytic genes. Cancer cell transformation is driven by mutations in tumor suppressor genes such as TP53 and STK11 and oncogenes such as KRAS and EGFR. In this study, SUV and FOXM1 gene expression were compared in the background of selected cancer gene mutations.
Methods
Archival tumor tissue from cases of lung adenocarcinoma were analyzed. SUV was collected from patient records. FOXM1 gene expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Gene mutations were detected by allele-specific PCR and gene sequencing.
Results
SUV and FOXM1 gene expression patterns differed in the presence of single and coexisting gene mutations. Gene mutations affected SUV and FOXM1 differently. EGFR mutations were found in tumors with lower FOXM1 expression but did not affect SUV. Tumors with TP53 mutations had increased SUV (p = .029). FOXM1 expression was significantly higher in tumors with STK11 mutations alone (p < .001) and in combination with KRAS or TP53 mutations (p < .001 and p = .002, respectively).
Conclusions
Cancer gene mutations may affect tumor metabolic activity. These observations support consideration of tumor cell metabolic state in the presence of gene mutations for optimal prognosis and treatment strategy.

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Prognostic value of combining clinical factors, 18F-FDG PET-based intensity, volumetric features, and deep learning predictor in patients with EGFR-mutated lung adenocarcinoma undergoing targeted therapies: a cross-scanner and temporal validation study
Kun-Han Lue, Yu-Hung Chen, Sung-Chao Chu, Chih-Bin Lin, Tso-Fu Wang, Shu-Hsin Liu
Annals of Nuclear Medicine.2024; 38(8): 647. CrossRef

MicroRNA-374a Expression as a Prognostic Biomarker in Lung Adenocarcinoma: Yeseul Kim, Jongmin Sim, Hyunsung Kim, Seong Sik Bang, Seungyun Jee, Sungeon Park, Kiseok Jang; J Pathol Transl Med. 2019;53(6):354-360. Published online October 24, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.01

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Abstract PDF

Background
Lung cancer is the most common cause of cancer-related death, and adenocarcinoma is the most common histologic subtype. MicroRNA is a small non-coding RNA that inhibits multiple target gene expression at the post-transcriptional level and is commonly dysregulated in malignant tumors. The purpose of this study was to analyze the expression of microRNA-374a (miR-374a) in lung adenocarcinoma and correlate its expression with various clinicopathological characteristics.
Methods
The expression level of miR-374a was measured in 111 formalin-fixed paraffin-embedded lung adenocarcinoma tissues using reverse transcription-quantitative polymerase chain reaction assays. The correlation between miR-374a expression and clinicopathological parameters, including clinical outcome, was further analyzed.
Results
High miR-374 expression was correlated with advanced pT category (chi-square test, p=.004) and pleural invasion (chi-square test, p=.034). Survival analysis revealed that patients with high miR-374a expression had significantly shorter disease-free survival relative to those with low miR-374a expression (log-rank test, p=.032).
Conclusions
miR-374a expression may serve as a potential prognostic biomarker for predicting recurrence in early stage lung adenocarcinoma after curative surgery.

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Upregulated miR-374a-5p drives psoriasis pathogenesis through WIF1 downregulation and Wnt5a/NF-κB activation
Jing Ma, Lu Gan, Hongying Chen, Lihao Chen, Yu Hu, Chao Luan, Kun Chen, Jiaan Zhang
Cellular Signalling.2024; 119: 111171. CrossRef
Cell-free plasma miRNAs analysis for low invasive lung cancer diagnostics
M. Yu. Konoshenko, P. P. Laktionov, Yu. A. Lancuhaj, S. V. Pak, S. E. Krasilnikov, O. E. Bryzgunova
Advances in Molecular Oncology.2023; 10(2): 78. CrossRef
MicroRNA‑mediated regulation in lung adenocarcinoma: Signaling pathways and potential therapeutic implications (Review)
Jiye Liu, Fei Zhang, Jiahe Wang, Yibing Wang
Oncology Reports.2023;[Epub] CrossRef
Dysregulation of miR-374a is involved in the progression of diabetic retinopathy and regulates the proliferation and migration of retinal microvascular endothelial cells
Zhanhong Wang, Xiao Zhang, Yanjun Wang, Dailing Xiao
Clinical and Experimental Optometry.2022; 105(3): 287. CrossRef
MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer
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p40 Immunohistochemistry Is an Excellent Marker in Primary Lung Squamous Cell Carcinoma: Khairunisa Ahmad Affandi, Nur Maya Sabrina Tizen, Muaatamarulain Mustangin, Reena Rahayu MdReena Rahayu Md Zin; J Pathol Transl Med. 2018;52(5):283-289. Published online August 31, 2018; DOI: https://doi.org/10.4132/jptm.2018.08.14

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Abstract PDF

Background
Lung cancer is the third most common cancer worldwide. With major advances in the molecular testing of lung cancers and the introduction of targeted therapies, the distinction between adenocarcinoma and squamous cell carcinoma as well as pathologic subtyping has become important. Recent studies showed that p40 is highly specific for squamous and basal cells and is superior to p63 for diagnosing lung squamous cell carcinoma. The aim of this study was to evaluate the use of p40 immunohistochemical stain in the diagnosis of non-small cell lung carcinoma and its potential to replace current p63 antibody as the best immunohistochemical squamous marker.
Methods
Seventy formalin-fixed paraffin-embedded cases previously diagnosed as primary lung squamous cell carcinoma (n = 35) and lung adenocarcinoma (n = 35) from January 2008 to December 2016 were retrieved. The results of tumour cell immunoreactivity for p40 and p63 antibodies in lung squamous cell carcinoma and lung adenocarcinoma were compared.
Results
p40 was expressed in 27 cases of lung squamous cell carcinoma (77.1%). All cases of lung adenocarcinoma (35/35, 100%) were negative for p40. p63 expression was positive in 30 cases of lung squamous cell carcinoma (85.7%) and 13 cases of lung adenocarcinoma (37.1%). Reactivity for both p40 and p63 in lung squamous cell carcinoma was strong and diffuse, whereas variable reactivity was observed in lung adenocarcinoma.
Conclusions
p40 is an excellent marker for distinguishing lung squamous cell carcinoma from adenocarcinoma, and p40 expression is equivalent to p63 expression in lung squamous cell carcinoma.

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Differential MicroRNA Expression between EGFR T790M and L858R Mutated Lung Cancer: Ji Yeon Kim, Woo Jeong Lee, Ha Young Park, Ahrong Kim, Dong Hoon Shin, Chang Hun Lee; J Pathol Transl Med. 2018;52(5):275-282. Published online August 16, 2018; DOI: https://doi.org/10.4132/jptm.2018.07.29

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Abstract PDF Supplementary Material

Background
MicroRNAs (miRNAs) are short, non-coding RNAs that mediate post-transcriptional gene regulation. They are commonly deregulated in human malignancies, including non-small cell lung cancer (NSCLC). The aim of this study is to investigate miRNA expression in T790M-mutated NSCLC resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.
Methods
Six cases of resected NSCLC harboring the T790M mutation were examined. We performed miRNA time polymerase chain reaction (PCR) array profiling using EGFR T790M-mutated NSCLC and L858R-mutated NSCLC. Once identified, miRNAs that were differentially expressed between the two groups were validated by quantitative real-time polymerase chain reaction (qRT-PCR).
Results
miRNA PCR array profiling revealed three up-regulated miRNAs whose expression levels were altered 4.0-fold or more in the EGFR T790M mutation group than in the L858R group: miR-1 (fold change, 4.384), miR-196a (fold change, 4.138), and miR-124 (fold change, 4.132). The three differentially expressed miRNAs were validated by qRT-PCR, and they were found to be overexpressed in the T790M group relative to L858R group. In particular, expression levels of miR-1 and miR-124 were significantly higher in the T790M group (p-value of miR-1 = .004, miR-124 = .007, miR-196a = .096).
Conclusions
MiR-1, miR-124, and miR-196a are overexpressed in EGFR T790M mutated NSCLC.

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Hao Ho, Sung-Liang Yu, Hsuan-Yu Chen, Shin-Sheng Yuan, Kang-Yi Su, Yi-Chiung Hsu, Chung-Ping Hsu, Cheng-Yen Chuang, Ya-Hsuan Chang, Yu-Cheng Li, Chiou-Ling Cheng, Gee-Chen Chang, Pan-Chyr Yang, Ker-Chau Li
Lung Cancer.2023; 184: 107352. CrossRef
Dynamic Evaluation of Circulating miRNA Profile in EGFR-Mutated NSCLC Patients Treated with EGFR-TKIs
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WITHDRAWN:A Clinicopathologic Study of 220 Cases of Pulmonary Sclerosing Pneumocytoma in Korea: A Nationwide Survey: Myunghee Kang, Seung Yeon Ha, Joung Ho Han, Mee Sook Roh, Se Jin Jang, Hee Jin Lee, Heae Surng Park, Geon Kook Lee, Kyo Young Lee, Jin-Haeng Chung, Yoo Duk Choi, Chang Hun Lee, Lucia Kim, Myoung Ja Chung, Soon Hee Jung, Gou Young Kim, Wan-Seop Kim; Received April 4, 2018 Accepted July 9, 2018 Published online July 16, 2018; DOI: https://doi.org/10.4132/jptm.2018.07.10 [Accepted]

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Review

Molecular Testing of Lung Cancers: Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee; J Pathol Transl Med. 2017;51(3):242-254. Published online April 21, 2017; DOI: https://doi.org/10.4132/jptm.2017.04.10

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Abstract PDF

Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories—mutations, gene rearrangements, and amplifications—and propose expanded guidelines on molecular testing of lung cancers.

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Original Article

Transformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases: Soomin Ahn, Soo Hyun Hwang, Joungho Han, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn, Woong-Yang Park; J Pathol Transl Med. 2016;50(4):258-263. Published online May 10, 2016; DOI: https://doi.org/10.4132/jptm.2016.04.19

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Abstract 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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Case Study

Sclerosing Perivascular Epithelioid Cell Tumor of the Lung: A Case Report with Cytologic Findings: Ha Yeon Kim, Jin Hyuk Choi, Hye Seung Lee, Yoo Jin Choi, Aeree Kim, Han Kyeom Kim; J Pathol Transl Med. 2016;50(3):238-242. Published online April 11, 2016; DOI: https://doi.org/10.4132/jptm.2016.02.19

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Abstract PDF

Benign perivascular epithelioid cell tumor (PEComa) of the lung is a rare benign neoplasm, a sclerosing variant of which is even rarer. We present a case of 51-year-old man who was diagnosed with benign sclerosing PEComa by percutaneous fine needle aspiration cytology and biopsy. The aspirate revealed a few cell clusters composed of bland-looking polygonal or spindle cells with fine granular or clear cytoplasm. Occasional fine vessel-like structures with surrounding hyalinized materials were seen. The patient later underwent wedge resection of the lung. The histopathological study of the resected specimen revealed sheets of polygonal cells with clear vacuolated cytoplasm, variably sized thin blood vessels, and densely hyalinized stroma. In immunohistochemical studies, reactivity of tumor cells for human melanoma black 45 and Melan-A further supported the diagnosis of benign sclerosing PEComa. To the best of our knowledge, this is the first case of benign sclerosing PEComa described in lung.

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Original Article

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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Abstract 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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Review

The Utilization of Cytologic Fine-Needle Aspirates of Lung Cancer for Molecular Diagnostic Testing: Michael H. Roh; J Pathol Transl Med. 2015;49(4):300-309. Published online June 16, 2015; DOI: https://doi.org/10.4132/jptm.2015.06.16

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Abstract PDF

In this era of precision medicine, our understanding and knowledge of the molecular landscape associated with lung cancer pathogenesis continues to evolve. This information is being increasingly exploited to treat advanced stage lung cancer patients with tailored, targeted therapy. During the management of these patients, minimally invasive procedures to obtain samples for tissue diagnoses are desirable. Cytologic fine-needle aspirates are often utilized for this purpose and are important not only for rendering diagnoses to subtype patients’ lung cancers, but also for ascertaining molecular diagnostic information for treatment purposes. Thus, cytologic fine-needle aspirates must be utilized and triaged judiciously to achieve both objectives. In this review, strategies in utilizing fine-needle aspirates will be discussed in the context of our current understanding of the clinically actionable molecular aberrations underlying non-small cell lung cancer and the molecular assays applied to these samples in order to obtain treatment-relevant molecular diagnostic information.

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Original Article

KRAS Mutation Detection in Non-small Cell Lung Cancer Using a Peptide Nucleic Acid-Mediated Polymerase Chain Reaction Clamping Method and Comparative Validation with Next-Generation Sequencing: Boram Lee, Boin Lee, Gangmin Han, Mi Jung Kwon, Joungho Han, Yoon-La Choi; Korean J Pathol. 2014;48(2):100-107. Published online April 28, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.2.100

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Abstract PDF

Background

KRAS is one of commonly mutated genetic "drivers" in non-small cell lung cancers (NSCLCs). Recent studies indicate that patients with KRAS-mutated tumors do not benefit from adjuvant chemotherapy, so there is now a focus on targeting KRAS-mutated NSCLCs. A feasible mutation detection method is required in order to accurately test for KRAS status.

Methods

We compared direct Sanger sequencing and the peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping method in 134 NSCLCs and explored associations with clinicopathological factors. Next-generation sequencing (NGS) was used to validate the results of discordant cases. To increase the resolution of low-level somatic mutant molecules, PNA-mediated PCR clamping was used for mutant enrichment prior to NGS.

Results

Twenty-one (15.7%) cases were found to have the KRAS mutations using direct sequencing, with two additional cases by the PNA-mediated PCR clamping method. The frequencies of KRAS mutant alleles were 2% and 4%, respectively, using conventional NGS, increasing up to 90% and 89%, using mutant-enriched NGS. The KRAS mutation occurs more frequently in the tumors of smokers (p=.012) and in stage IV tumors (p=.032).

Conclusions

Direct sequencing can accurately detect mutations, but, it is not always possible to obtain a tumor sample with sufficient volume. The PNA-mediated PCR clamping can rapidly provide results with sufficient sensitivity.

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